Suggestive linkage of situs inversus and other left-right axis anomalies to chromosome 6p.
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Body Patterning↗
Biomedical subjects
J Weber
Publications and source records attributed to J Weber.
A phase I study of CNI-1493, an inhibitor of cytokine release, in combination with high-dose interleukin-2 in patients with renal cancer and melanoma.
CNI-1493, an inhibitor of proinflammatory cytokines, was studied in a Phase I trial in melanoma and renal cancer patients receiving high-dose interleukin 2 (IL-2). Objectives of the study were to define the maximum tolerated dose (MTD) and toxicity of CNI-1493, to assess its pharmacological effects, and to define its pharmacokinetics. Twenty-four patients were treated in sequential cohorts with CNI-1493 doses from 2 through 32 mg/m2 daily. Patients first received only CNI-1493 daily for 5 days. After a 9-day rest, patients received two 5-day courses of IL-2 of 600,000 IU/kg every 8 h for up to 14 doses/course plus daily CNI-1493; courses were separated by a 9-day rest period. CNI-1493 administered alone was well tolerated at doses through 32 mg/m2; MTD was not reached. The only clinical toxicity attributed to CNI-1493 was occasional injection-site phlebitis. Grade 1 creatinine increases occurred in 1 of 7 patients at 4 mg/m2, in 1 of 1 patients at 25 mg/m2, and in 3 of 6 patients at 32 mg/m2 CNI-1493 alone. In combination with high-dose IL-2, CNI-1493 at > or = 25 mg/m2 seemed to exacerbate IL-2-induced nephrotoxicity: grade 3 or 4 creatinine increases developed in 3 of 6 patients at 25 or 32 mg/m2, as compared with 1 of 16 patients at doses < or = 16 mg/m2. The MTD for CNI-1493 given with high-dose IL-2 was 16 mg/m2. The dose-limiting toxicity of IL-2 was hypotension in 63% of patients; overall tolerance to IL-2 was not improved by CNI-1493. However, relative to changes seen in a reference group receiving high-dose IL-2 alone, at doses > or = 4 mg/m2 CNI-1493 did show evidence of pharmacological activity as an inhibitor of tumor necrosis factor production.
Adult↗
[Evaluation of clinical competence in gynecology obstetrics: an innovative approach using the Objective Structured Clinical Examination].
OBJECTIVE: The evaluation of medical student clinical competence in Obstetrics and Gynaecology using Objective Structured Clinical Examination (OSCE). MATERIAL AND METHODS: Development of OSCE with definition of an assessment of subject, choice of clinical stations sampling, identification of components of clinical competence to be evaluated, the level of performance required, development of specification table, editing of OSCE presentation page and assessment of praticability and results exploitation. RESULTS: Eleven station stimuli with simulated patient participation were carried out, 2 stations with a mannequin model and 1 questionnaire station. CONCLUSION: Our experience suggests OSCE feasibility for Obstetrics and Gynaecology during the initial course of education presents adequate psychometric characteristics. This gold standard can no longer be overlooked and should be considered as a useful tool to assess medical student competence. Nevertheless, OSCE remains to be further evaluated in France.
Clinical Competence↗
[Therapeutic efficacy during active phases of multiple sclerosis: gait analysis and comparison with the EDSS score].
Fifteen patients experiencing a flare-up of multiple sclerosis were given 1 g methylprednosolone per day for 5 days. The EDSS score and gait analysis using spatio-temporal variables were recorded for these patients on days 0, 5 and 45. Both methods evidenced significant improvement but the significance was observed between day 0 and day 5 for the EDSS and between day 5 and 45 for gait speed and between day 0 and 45 for step rate. Gait speed was correlated with the pyramidal scale but not with the other functional scales of the EDSS. These results suggest that EDSS and spatio-temporal gait analysis are different tools for the assessment of therapeutic effect. Gait analysis can provide a precise quantitative assessment of the locomotor handicap as a function of the proposed treatment.
Adult↗
Quantitative trait loci on chromosomes 3 and 17 influence phenotypes of the metabolic syndrome.
Recent research has emphasized the importance of the metabolic cluster, which includes glucose intolerance, dyslipidemia, and high blood pressure, as a strong predictor of the obesity-related morbidities and premature mortality. Fundamental to this association, commonly referred to as the metabolic syndrome, is the close interaction between abdominal fat patterning, total body adiposity, and insulin resistance. As the initial step in identifying major genetic loci influencing these phenotypes, we performed a genomewide scan by using a 10-centiMorgan map in 2,209 individuals distributed over 507 nuclear Caucasian families. Pedigree-based analysis using a variance components linkage model demonstrated a quantitative trait locus (QTL) on chromosome 3 (3q27) strongly linked to six traits representing these fundamental phenotypes [logarithm of odds (lod) scores ranged from 2.4 to 3.5]. This QTL exhibited possible epistatic interaction with a second QTL on chromosome 17 (17p12) strongly linked to plasma leptin levels (lod = 5.0). Situated at these epistatic QTLs are candidate genes likely to influence two biologic precursor pathways of the metabolic syndrome.
Blood Glucose↗
Can octahedral t2g6 complexes substitute associatively? The case of the isoelectronic ruthenium(II) and rhodium(III) hexaaquaions.
For the low-spin t2g6 Ru(OH2)6(2+) (delta V++ = -0.4 cm3 mol-1) and Rh(OH2)6(3+) (delta V++ = -4.2 cm3 mol-1) hexaaquaions, the respective Id and Ia water exchange mechanisms had been assigned, mainly on the basis of activation volumes delta V++ and entering ligands effects for water substitution. For Ru(II) the near-zero delta V++ was supposed to be due to the compensation between a positive contribution (the loss of a water molecule) and a negative one (the contraction of the bonds of the five spectator ligands at the transition state). Recently, it has been suggested that Rh(III), because of its higher positive charge, could promote further spectator ligands bond contraction sufficient to change the sign of delta V++ to a negative value. If true, this would be an example of limitation in the use of delta V++ for a direct diagnosis of the mechanism. Quantum chemical calculations including hydration effects show that the activation energies for the water exchange on Rh(OH2)6(3+) via the Ia (114.8 kJ mol-1) and the D pathways is 21.8 kJ mol-1 in favor of the former. In the case of Ru(OH2)6(2+) all attemps to compute a transition state for an interchange mechanism failed, but the calculated delta E++ for the D mechanism (71.9 kJ mol-1) is close to both experimental delta G298++ and delta H298++ values. The calculated delta sigma d(M-O) values of -0.53 A for rhodium(III) and +1.25 A for ruthenium(II) agree with the experimented delta V++ values and suggest Ia and D (or Id) mechanisms, respectively. In the case of Ru(OH2)6(2+) the shortening of the bonds of the five spectator ligands to reach the transition states corresponds to a volume change of -1.7 cm3 mol-1. For Rh(OH2)6(3+) these spectator ligands' volume decrease is much smaller (maximum of -0.8 cm3 mol-1) and the bond lengths of the two exchanging ligands at the transition state are characteristic of an interchange pathway with a small "a" character. Because of the strong RhIII-O bonds, water exchange on Rh(OH2)6(3+) proceeds via the Ia pathway with retention of the configuration, whereas the same reaction of Ru(OH2)6(2+), which has considerably weaker RuII-O bonds, follows the Id or the D mechanism.
Journal Article↗
Extended rodlike polyaromatic receptors with bent tridentate units complexed to lanthanide metal ions.
A synthetic strategy is developed to attach semirigid lipophilic sidearms to the 6-positions of bent aromatic tridentate 2,6-bis(benzimidazol-2-yl)pyridine cores to produce U-shaped ligands, L6,7. Differential scanning calorimetry (DSC) reveals that entropic contributions severely affect the isotropization processes of these flexible receptors, but no mesomorphism is detected. The attachment of oxygen linkers to the 5- or 6-positions of the benzimidazole sidearms lowers the ligand-centered 1 pi pi* and 3 pi pi* excited states, and the semiempirical ZINDO method assigns this effect to a destabilization of the HOMO orbitals resulting from pi-interactions. Reactions of L6 with Ln(NO3)3.xH2O provide the rodlike 1:1 complexes [Ln(L6)(NO3)3] (Ln = La-Lu), which are stable in the solid state but partially dissociate in acetonitrile. The crystal structure of [Lu(L6)(NO3)3].CH3CN (18a, LuC63H84N9O13, monoclinic, P2(1)/n, Z = 4) reveals an I-shaped arrangement of the ligand strand arising from the meridional complexation of the bent tridentate unit to nine-coordinate Lu(III). The replacement of nitrate anions with trifluoroacetate anions gives the centrosymmetric dimer [Lu(L6)(CF3CO2)3]2 (23, Lu2C134H162N10O20F18, triclinic, P1, Z = 1), in which the symmetry-related Lu atoms are connected by two bridging carboxylates, leading to an H-shaped dimetallic edifice. These complexes [Ln(L6)(NO3)3] and [Ln(L6)(CF3CO2)3]2 fulfill the geometrical criteria required by precursors of calamitic metallomesogens, but no mesomorphism can be detected, while photophysical studies indicate that the low energies of ligand-centered 3 pi pi* excited states drastically limit the luminescence of Eu(III) complexes. The relationships between structural and electronic properties resulting from 5- or 6-substitutions of the benzimidazole rings and the effects of these substitutions on photophysical and thermal properties are discussed.
Journal Article↗
Frobenius-perron resonances for maps with a mixed phase space
Resonances of the time evolution (Frobenius-Perron) operator P for phase space densities have recently been shown to play a key role for the interrelations of classical, semiclassical, and quantum dynamics. Efficient methods to determine resonances are thus in demand, in particular, for Hamiltonian systems displaying a mix of chaotic and regular behavior. We present a powerful method based on truncating P to a finite matrix which not only allows us to identify resonances but also the associated phase space structures. It is demonstrated to work well for a prototypical dynamical system.
Journal Article↗
ATP-driven rotation of the gamma subunit in F(1)-ATPase.
We present a mechanism for F(1)-ATPase in which hydrolysis of MgATP in the high-affinity catalytic site at the alpha/beta interface drives rotation of the gamma subunit via conformational changes in the alpha subunit. During hydrolysis, transition state formation and separation of P(i) from MgADP causes movement of portions of alpha, transmitted via two Arg residues which are hydrogen-bonded to the gamma-phosphate of MgATP, alphaArg376 and betaArg182; the latter is also hydrogen-bonded to interfacial alpha residues between alpha346 and alpha349. Changes in alpha conformation then push on gamma, resulting in rotation. Supporting evidence from the literature and from new data is discussed.
Adenosine Triphosphate↗
A picomolar inhibitor of resistant strains of human immunodeficiency virus protease identified by a combinatorial approach.
In order to identify inhibitors of various drug-resistant forms of the human immunodeficiency virus protease (HIV PR), we have designed and synthesized pseudopeptide libraries with a general structure Z-mimetic-Aa1-Aa2-NH2. Five different chemistries for peptide bond replacement have been employed and the resulting five individual sublibraries tested with the HIV PR and its drug-resistant mutants. Each mutant contains amino acid substitutions that have previously been shown to be associated with resistance to protease inhibitors, including Ritonavir, Indinavir, and Saquinavir. We have mapped the subsite preferences of resistant HIV PR species with the aim of selecting a pluripotent pharmaceutical lead. All of the enzyme species in this study manifest clear preference for an L-Glu residue in the P2' position. Slight, but significant, differences in P3' subsite specificity among individual resistant PR species have been documented. We have identified three compounds, combining the most favorable features of the inhibitor array, that exhibit low-nanomolar or picomolar Ki values for all three mutant PR species tested.
Combinatorial Chemistry Techniques↗
New probes of the F1-ATPase catalytic transition state reveal that two of the three catalytic sites can assume a transition state conformation simultaneously.
MgADP in combination with fluoroscandium (ScFx) is shown to form a potently inhibitory, tightly bound, noncovalent complex at the catalytic sites of F(1)-ATPase. The F(1).MgADP.ScFx complex mimics a catalytic transition state. Notably, ScFx caused large enhancement of MgADP binding affinity at both catalytic sites 1 and 2, with little effect at site 3. These results indicate that sites 1 and 2 may form a transition state conformation. A new direct optical probe of F(1)-ATPase catalytic transition state conformation is also reported, namely, substantial enhancement of fluorescence emission of residue beta-Trp-148 observed upon binding of MgADP.ScFx or MgIDP. ScFx. Using this fluorescence signal, titrations were performed with MgIDP.ScFx which demonstrated that catalytic sites 1 and 2 can both form a transition state conformation but site 3 cannot. Supporting data were obtained using MgIDP-fluoroaluminate. Current models of the MgATP hydrolysis mechanism uniformly make the assumption that only one catalytic site hydrolyzes MgATP at any one time. The fluorometal analogues demonstrate that two sites have the capability to form the transition state simultaneously.
Adenosine Diphosphate↗
Mosaic telomeric (2;14) association in a child with motor delay.
In a 6-year-old girl referred because of mild motor delay and hyperextensible joints, chromosome analysis disclosed a derivative chromosome consisting of end-to-end fusion of chromosomes 2 and 14. Two cell lines existed in which this telomere association was present, one with a 45,XX,tas(2;14)(q37;p11) karyotype and one with a 45,XX,tas(2;14) (q37;q32) karyotype. The cell line with the telomeric fusion of 2q and 14p was present in 90% of the cells; a telomeric fusion of 2q and 14q was seen in the remaining 10% of the cells. In both association complexes, only the centromere of chromosome 14 was active. Fluorescence in situ hybridization with telomere and subtelomere probes disclosed no deletion of chromosomal material. Microsatellite analysis showed that the patient had a normal biparental contribution of chromosomes 14.
Child↗
ATP synthase: what we know about ATP hydrolysis and what we do not know about ATP synthesis.
In ATP synthase, X-ray structures, demonstration of ATP-driven gamma-subunit rotation, and tryptophan fluorescence techniques to determine catalytic site occupancy and nucleotide binding affinities have resulted in pronounced progress in understanding ATP hydrolysis, for which a mechanism is presented here. In contrast, ATP synthesis remains enigmatic. The molecular mechanism by which ADP is bound in presence of a high ATP/ADP concentration ratio is a fundamental unknown; similarly P(i) binding is not understood. Techniques to measure catalytic site occupancy and ligand binding affinity changes during net ATP synthesis are much needed. Relation of these parameters to gamma-rotation is a further goal. A speculative model for ATP synthesis is offered.
Adenosine Diphosphate↗
Features of F(1)-ATPase catalytic and noncatalytic sites revealed by fluorescence lifetimes and acrylamide quenching of specifically inserted tryptophan residues.
Catalytic and noncatalytic nucleotide sites of the F(1) sector of ATP synthase were characterized by tryptophan fluorescence techniques. Seven Trp residues inserted in varied microenvironments in the catalytic sites, and one in the noncatalytic sites, were studied in mutant F(1) enzymes which were otherwise devoid of Trp. Parameters measured were fluorescence lifetimes and dynamic and static quenching by acrylamide in the absence or presence of nucleotide. The results indicated that the solution structures of the mutant enzymes were consistent with reported crystal structures. In enzyme with three empty noncatalytic sites, all sites were relatively inaccessible to acrylamide, indicating a closed conformation. In contrast, when the three catalytic sites were empty, they were relatively and equally accessible to acrylamide, indicating an open conformation. This was the case in the presence or absence of Mg(2+). Residue beta-Trp-331 has been extensively used previously to determine nucleotide binding parameters in F(1). Results here showed that in betaY331W mutant F(1), each of the three beta-Trp-331 residues has an unusually long fluorescence lifetime, confirming that each contributes equally to the overall fluorescence signal.
Acrylamide↗
An improved algorithm for determining HIV type 1 subtypes in a primary laboratory in Uganda.
A pilot study was undertaken with the objective of developing a simple, economical, and efficient algorithm through which to subtype HIV-1 in a large epidemiological cohort study in Uganda. A peptide enzyme immunoassay (PEIA) employing both V3 and gp41 regions and a heteroduplex mobility assay (HMA) were evaluated in comparison with DNA sequencing. Of 146 samples selected, 115 (79%) were successfully sequenced. Taking sequence data as the "gold standard," other assays were compared with these data. The HMA correctly identified 95 (83%) of the samples, and only 1 sample was wrongly identified. The V3 PEIA alone and in combination with gp41 peptides correctly identified 76 and 78% of the samples, respectively; however, the number of wrongly identified samples was four times less with the combination compared with V3 peptides alone (4 versus 16%). The sensitivity, specificity, and positive and negative predictive values for serotype A and D samples were greater for the combination than V3 peptides alone. We have described a new algorithm to segregate subtypes A and D. This algorithm uses the two peptide assays followed by HMA and then DNA sequencing for untypable samples, giving an accuracy of 95% at a cost of 37 and 21% for consumables compared with subtyping all the samples by HMA or DNA sequencing, respectively. This proposed approach is suitable for epidemiological studies in Uganda and other regions with a predominance of A and D subtypes.
Algorithms↗
A phase I trial in HIV negative healthy volunteers evaluating the effect of potent adjuvants on immunogenicity of a recombinant gp120W61D derived from dual tropic R5X4 HIV-1ACH320.
Thirty healthy HIV negative volunteers were randomised to receive 200 micrograms of rgp120W61D in either: 3D-MPL and QS21, with an oil and water emulsion (SBAS-2) (13); or 3D-MPL and QS21 (SBAS-1) (11); or alum (six). Immunizations were given at 0, 4 and 28 weeks and 23 (77%) participants completed the schedule. Adverse events were more frequent (P < 0.001) and more severe (P < 0.001) in the SBAS-2 group. Binding antibodies to the homologous rgp120W61D were detected after the first immunisation only in those receiving SBAS-1 and SBAS-2, were maximal after the third immunization in all three groups, and persisted to week 84 only in the novel adjuvant groups. These differences were significant (p = 0.02). Neutralising antibodies to TCLA-strains of HIV-1 were observed after the second immunization in all three groups, were maximal after the third immunization, but did not neutralise homologous or heterologous PBMC derived primary HIV-1 isolates. Proliferative T-cell responses to rgp120W61D were maximal after the second immunization and reached very high values in the SBAS-2 group. HIV-1 specific CD8+ MHC Class I restricted cytotoxic T-lymphocytes were not seen in a subset of participants tested at a single timepoint. SBAS-2 with rgp120W61D induced antibody titres as high as those seen in HIV infection, but the quality of the antibodies remained different in that there was no evidence of primary isolate neutralisation. Although cell-mediated immunity was enhanced by SBAS-2 in terms of lymphoproliferative responses, HIV-1 specific CD8+ cytotoxicity was not demonstrated.
AIDS Vaccines↗
Diffusion-weighted imaging in ischaemic stroke: a follow-up study.
Diffusion-weighted (DWI) echo-planar (EPI) MRI has been used for imaging acute ischaemic stroke. We used DWI and conventional spin-echo (SE) MRI to study the dynamics of ischaemic human stroke. We examined 30 patients (mean age 57.5 years, range 27-82 years, median 57 years) with a diagnosis of stroke. They were examined in the acute (120 min to 47 h, mean 15.3 h), subacute (8 days) and chronic (2-3 months) stages of ischaemia using clinical scores and MRI. Imaging was performed on an 1.5-T imager. Anisotropic DWI with diffusion gradients in all three axes, an isotropic tensor trace pulse DWI sequence and SE MRI were used. In all patients both DWI sequences showed a decrease in the apparent diffusion coefficient (ADC) in the acute stage, even when SE images did not reveal signal abnormalities. Clinical features correlated with lesion site but not size. The ADC was initially 19.6-43% less than that of nonischaemic tissue and increased to normal after 7 days in conventionally treated patients and after 2-5 days in patients who underwent intra-arterial fibrinolysis. In the chronic stage the ADC rose by up to 254.4 %. In patients who did not undergo fibrinolysis DWI changes correlated with the final infarct size (P<0.05). It was possible to differentiate acute from chronic ischaemic lesions. We conclude that DWI is a sensitive and practicable tool for detecting early cerebral ischaemia. It is possible to predict in the acute stage the final size of an infarct. DWI may be helpful for clinical decisions and for monitoring therapy.
Brain↗
[Blue-yellow perimetry in rhegmatogenous retinal detachment. Studies before and after therapy in comparison with white-white perimetry].
INTRODUCTION: Disturbance of the blue light perceptance in rhegmatogenous retinal detachment was demonstrated by Köllner 1907 with the help of colour-perimetries. We examined the blue- and white-function after retinal reattachment by blue-on-yellow-perimetry compared with white-on-white-perimetry. PATIENTS AND METHODS: 10 Patients with rhegmatogenous retinal detachment and a visual acuity > or = 0.1 were examined preoperatively, 4 days and 6 weeks after successful buckling procedure. We performed a white-on-white-perimetry as also perimetries with blue stimuli on a yellow luminance background (program 30-2 of the Humphrey Field Analyzer 750). RESULTS: Four days after surgery the increase in sensitivity was significantly less for the blue-function compared with the white-function. Preoperatively and 6 weeks postoperatively the sensitivities were not significantly different. Between these time-points function recovered in average for both methods from MD -15 dB to MD -5 dB. CONCLUSION: After successful retinal detachment surgery the blue- and white-function increased. Blue-on-yellow-perimetry showed more retinal sensitivity loss than white-on-white-perimetry immediately after surgery. Blue-on-yellow-perimetry measured the same retinal sensitivity loss as white-on-white-perimetry preoperatively and 6 weeks postoperatively.
Adult↗