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Biomedical subjects

R Kahn

Publications and source records attributed to R Kahn.

At least 19 recordsLinked to original sources
PubMed2005

The metabolic syndrome: time for a critical appraisal. Joint statement from the American Diabetes Association and the European Association for the Study of Diabetes.

BACKGROUND: The term 'metabolic syndrome' refers to a clustering of specific cardiovascular disease (CVD) risk factors whose underlying pathophysiology is thought to be related to insulin resistance. METHODS: Since the term is widely used in research and clinical practice, we undertook an extensive review of the literature in relation to the syndrome's definition, underlying pathogenesis, association with cardiovascular disease and to the goals and impact of treatment. DISCUSSION: While there is no question that certain CVD risk factors are prone to cluster, we found that the metabolic syndrome has been imprecisely defined, there is a lack of certainty regarding its pathogenesis, and there is considerable doubt regarding its value as a CVD risk marker. Our analysis indicates that too much critically important information is missing to warrant its designation as a 'syndrome'. CONCLUSION: Until much-needed research is completed, clinicians should evaluate and treat all CVD risk factors without regard to whether a patient meets the criteria for diagnosis of the 'metabolic syndrome'.

Body Mass Index↗
PubMed2004

Structural and functional studies of FkpA from Escherichia coli, a cis/trans peptidyl-prolyl isomerase with chaperone activity.

The protein FkpA from the periplasm of Escherichia coli exhibits both cis/trans peptidyl-prolyl isomerase (PPIase) and chaperone activities. The crystal structure of the protein has been determined in three different forms: as the full-length native molecule, as a truncated form lacking the last 21 residues, and as the same truncated form in complex with the immunosuppressant ligand, FK506. FkpA is a dimeric molecule in which the 245-residue subunit is divided into two domains. The N-terminal domain includes three helices that are interlaced with those of the other subunit to provide all inter-subunit contacts maintaining the dimeric species. The C-terminal domain, which belongs to the FK506-binding protein (FKBP) family, binds the FK506 ligand. The overall form of the dimer is V-shaped, and the different crystal structures reveal a flexibility in the relative orientation of the two C-terminal domains located at the extremities of the V. The deletion mutant FkpNL, comprising the N-terminal domain only, exists in solution as a mixture of monomeric and dimeric species, and exhibits chaperone activity. By contrast, a deletion mutant comprising the C-terminal domain only is monomeric, and although it shows PPIase activity, it is devoid of chaperone function. These results suggest that the chaperone and catalytic activities reside in the N and C-terminal domains, respectively. Accordingly, the observed mobility of the C-terminal domains of the dimeric molecule could effectively adapt these two independent folding functions of FkpA to polypeptide substrates.

Amino Acid Sequence↗
PubMed2003

Molecular mobility of confined phases in model mesoporous (MCM-41) and microporous (AlPO(4)-5 zeolite) host materials.

The considered host materials are well suited to confine quasi-(1d) molecular phases, seeing that their porosities are composed of parallel unconnected cylindrical pores. For such a simple geometry, confinement effects can be simply described by a single parameter, the pore diameter phi. Our study concerns medium and ultra confinement ranges ( 40 A >or= Ø >or= 7.3 A). The primary effect of such confinements is the decrease of the molecular interactions within the confined phase. As a consequence, we have observed strong triple point depressure Delta T(3t) effects for hydrogen and water confined phases in MCM-41 samples. In the limit case of (1d) phase (the neopentane/AlPO(4)-5 system) it seems that a molecular mobility is observed even at very low temperature T=5 K. The secondary confinement effect is an increase of the interactions between the host inner surface and the confined molecular assembly induced by the pore diameter decreasing. Such host material influence gives rise, for medium range confinement to the physisorption of a curved solid film on the inner surface before the capillary phase condensation (hydrogen/MCM-41 (24 A)) and for ultra confinement to the solidification of the confined phase when the molecular species are commensurate with the inner surface sites (methane/AlPO(4)-5).

Journal Article↗
PubMed2003

High-phasing-power lanthanide derivatives: taking advantage of ytterbium and lutetium for optimized anomalous diffraction experiments using synchrotron radiation.

Ytterbium and lutetium are well suited for optimized anomalous diffraction experiments using synchrotron radiation. Therefore, two lanthanide complexes Yb-HPDO3A and Lu-HPDO3A have been produced that are similar to the Gd-HPDO3A complex already known to give good derivative crystals. Derivative crystals of hen egg-white lysozyme were obtained by co-crystallization using 100 mM solutions of each lanthanide complex. De novo phasing has been carried out using single-wavelength anomalous diffraction on data sets collected on each derivative crystal at the L(III) absorption edge of the corresponding lanthanide (ff" = 28 e(-)). A third data set was collected on a Lu-HPDO3A derivative crystal at the Se K absorption edge with f"(Lu) = 10 e(-). The structures were refined and compared with the known structure of the Gd-HPDO3A lysozyme derivative. The quality of the experimental electron-density maps allows easy model building. With L(III) absorption edges at shorter wavelengths than the gadolinium absorption edge, lutetium and ytterbium, when chelated by a ligand such as HPDO3A, form lanthanide complexes that are especially interesting for synchrotron-radiation experiments in structural biology.

Animals↗
PubMed2003

Three-dimensional structure of FEZ-1, a monomeric subclass B3 metallo-beta-lactamase from Fluoribacter gormanii, in native form and in complex with D-captopril.

The beta-lactamases are involved in bacterial resistance to penicillin and related compounds. Members of the metallo-enzyme class are now found in many pathogenic bacteria and are thus becoming of major clinical importance. The structures of the Zn-beta-lactamase from Fluoribacter gormanii (FEZ-1) in the native and in the complex form are reported here. FEZ-1 is a monomeric enzyme, which possesses two zinc-binding sites. These structures are discussed in comparison with those of the tetrameric L1 enzyme produced by Stenotrophomonas maltophilia. From this analysis, amino acids involved in the oligomerization of L1 are clearly identified. Despite the similarity in fold, the active site of FEZ-1 was found to be significantly different. Two residues, which were previously implicated in function, are not present in L1 or in FEZ-1. The broad-spectrum substrate profile of Zn-beta-lactamases arises from the rather wide active-site cleft, where various beta-lactam compounds can be accommodated.

Amino Acid Sequence↗
PubMed2002

A new class of gadolinium complexes employed to obtain high-phasing-power heavy-atom derivatives: results from SAD experiments with hen egg-white lysozyme and urate oxidase from Aspergillus flavus.

Seven gadolinium complexes are shown to be excellent compounds for the preparation of heavy-atom derivatives for macromolecular crystallography projects. De novo phasing has been carried out using single-wavelength anomalous diffraction (SAD) on a series of gadolinium-derivative crystals of two proteins: hen egg-white lysozyme and urate oxidase from Aspergillus flavus. Lysozyme derivative crystals were obtained by co-crystallizing the protein with the corresponding gadolinium complex at a concentration of 100 mM. Diffraction data were collected to a resolution of 1.7 A using Cu K(alpha) radiation from a rotating-anode generator, making use of the high anomalous signal of gadolinium at this wavelength. Urate oxidase derivative crystals were obtained by soaking native crystals in 100 mM gadolinium complex solutions. Diffraction data were collected to a resolution close to 3 A using X-rays at the Gd L(III) absorption edge, taking advantage of the sharp white line on that edge. For all urate oxidase derivative crystals and three of the lysozyme crystals, SAD phasing led to electron-density maps of very high quality, allowing unambiguous chain tracing. From this study, the binding effectiveness of the gadolinium complexes seems to be related to the nature of the precipitant used for crystallization. These gadolinium complexes represent a new class of high-phasing-power heavy-atom derivatives that may be used for high-throughput structure-determination projects.

Animals↗
PubMed2002

FIP: a highly automated beamline for multiwavelength anomalous diffraction experiments.

FIP is a French Collaborating Research Group (CRG) beamline at the European Synchrotron Radiation Facility (ESRF) dedicated exclusively to crystallography of biological macromolecules, with a special emphasis on multiwavelength anomalous diffraction data collection in the 0.7-1.81 A wavelength range. The optics, consisting of long cylindrical grazing-angle mirrors associated with a cryocooled double-crystal monochromator, delivers an optimal beam in the corresponding energy range. The high level of automation, which includes automated crystal centring, automated data-collection management and data processing, makes the use of this beamline very easy. This is illustrated by the large number of challenging structures that have been solved since 1999.

Automation↗
PubMed2002

Use of illicit substances in a psychosis incidence cohort: a comparison among different ethnic groups in the Netherlands.

OBJECTIVE: Use of illicit substances has been suggested as an explanation for the increased incidence of psychosis among some immigrant groups. The aim of the present study is to compare the rates of illicit substance use among immigrants with a first psychosis with that among non-migrants. METHOD: A population-based, first-contact incidence study in the Netherlands. Patients and key informants were interviewed about drug use in the preceding year. RESULT: One hundred and eighty-one subjects were examined. Proportions of patients who misused any illicit substance were 23% for Dutch, 17% for Moroccans, 27% for Surinamese, 30% for Turkish subjects, and 33% for other immigrants. Logistic regression analysis, controlling for age and sex, showed that ethnicity did not significantly contribute to the prediction of substance misuse. CONCLUSION: A higher rate of drug misuse is an unlikely explanation for the increased incidence of psychotic disorders among Moroccan and Surinamese immigrants to the Netherlands.

Adult↗
PubMed2001

High-pressure protein crystallography (HPPX): instrumentation, methodology and results on lysozyme crystals.

A new set-up and associated methodology for the collection of angle-dispersive diffraction data from protein crystals submitted to high hydrostastic pressure have been developed on beamline ID30 at the ESRF. The instrument makes use of intense X-rays of ultra-short wavelength emitted by two collinear undulators, and combines a membrane-driven diamond-anvil cell mounted on a two-axis goniometer and an imaging-plate scanner. Sharp and clean diffraction pictures from tetragonal crystals of hen egg-white lysozyme (tHEWL) and orthorhombic crystals of bovine erythrocyte Cu, Zn superoxide dismutase (SOD) were recorded at room temperature and pressures up to 0.915 and 1.00 GPa, respectively. The compressibility of tHEWL was determined from unit-cell parameters determined at 24 different pressures up to 0.915 GPa. High-pressure diffraction data sets from several crystals of tHEWL were collected and analyzed. Merging of data recorded on different crystals at 0.30 and 0.58 GPa produced two sets of structure amplitudes with good resolution, completeness, redundancy and R(sym) values. A third set at 0.69 GPa was of a similar quality except a lower completeness. The three structures have been refined. The pressure-induced loss of crystalline order in a tHEWL crystal beyond 0.82 GPa was captured through a series of diffraction pictures.

Crystallization↗
PubMed2001

CYP94A5, a new cytochrome P450 from Nicotiana tabacum is able to catalyze the oxidation of fatty acids to the omega-alcohol and to the corresponding diacid.

A full length cDNA encoding a new cytochrome P450-dependent fatty acid hydroxylase (CYP94A5) was isolated from a tobacco cDNA library. CYP94A5 was expressed in S. cerevisiae strain WAT11 containing a P450 reductase from Arabidopsis thaliana necessary for catalytic activity of cytochrome P450 enzymes. When incubated for 10 min in presence of NADPH with microsomes of recombinant yeast, 9,10-epoxystearic acid was converted into one major metabolite identified by GC/MS as 18-hydroxy-9,10-epoxystearic acid. The kinetic parameters of the reaction were Km,app = 0.9 +/- 0.2 microM and Vmax,app = 27 +/- 1 nmol x min(-1) x nmol(-1) P450. Increasing the incubation time to 1 h led to the formation of a compound identified by GC/MS as 9,10-epoxy-octadecan-1,18-dioic acid. The diacid was also produced in microsomal incubations of 18-hydroxy-9,10-epoxystearic acid. Metabolites were not produced in incubations with microsomes of yeast transformed with a control plasmid lacking CYP94A5 and their production was inhibited by antibodies raised against the P450 reductase, demonstrating the involvement of CYP94A5 in the reactions. The present study describes a cytochrome P450 able to catalyze the complete set of reactions oxidizing a terminal methyl group to the corresponding carboxyl. This new fatty acid hydroxylase is enantioselective: after incubation of a synthetic racemic mixture of 9,10-epoxystearic acid, the chirality of the residual epoxide was 40/60 in favor of 9R,10S enantiomer. CYP94A5 also catalyzed the omega-hydroxylation of saturated and unsaturated fatty acids with aliphatic chain ranging from C12 to C18.

Alcohols↗
PubMed2001

The Interdisciplinary Generalist Curriculum (IGC) project: an overview of its experience and outcomes.

The Interdisciplinary Generalist Curriculum (IGC) Project was a competitive, seven-year demonstration project funded by the Health Resources and Services Administration (HRSA). It was established to determine whether specific interdisciplinary innovations in preclinical medical school curricula could affect students' selection of careers in family medicine, general internal medicine, or general pediatrics. Through collaboration among the three generalist disciplines, the IGC innovation exposed all preclinical students in ten demonstration schools to a new or significantly enhanced preclinical curriculum that included a direct supervised clinical experience with a generalist physician preceptor. The project was managed by an interdisciplinary executive committee that was codirected by one representative each from family medicine, general internal medicine, and general pediatrics. A national advisory committee with representation from the academic and professional organizations of family medicine, internal medicine, pediatrics, and osteopathy provided input to the executive committee in guiding the project. The project was externally evaluated. Major outcomes of the IGC Project include sustained curricular changes in ten institutions, prompted by relatively few dollars and demonstration of models for collaboration at institutional and national levels. This supplement describes the IGC Project's experience and outcomes so that others may draw pertinent information to apply to their own efforts in medical education.

Curriculum↗
PubMed2001

From the primary care organizations consortium's proposal to the Interdisciplinary Generalist Curriculum Project.

The Interdisciplinary Generalist Curriculum (IGC) Project was one element of an overall federal government strategy designed to promote primary care education. This project, undertaken by the Division of Medicine and Dentistry (DMD), Bureau of Health Professions, Health Resources and Services Administration, U.S. Department of Health and Human Services, was the first large-scale medical education contract initiated by DMD. The IGC Project was based on a model proposed by the Primary Care Organizations Consortium (PCOC). The PCOC thesis was that "if students are to decide to pursue a generalist career they must have the opportunity to be taught by generalists." The PCOC Program required an explicit curriculum focusing on generalist knowledge and skills with an emphasis on technology, in the context of education that required training in ambulatory office-based settings. The PCOC Program specified that responsibility for the program's planning, implementation, and evaluation be shared by the three generalist physician faculties of family medicine, general internal medicine, and general pediatrics. In implementation of this demonstration project in ten medical schools across the nation, several lessons have been learned relative to enhancement of generalist education. Among these lessons is that seed money targeted to initiate modest change can act as a catalyst and improve the knowledge and skills afforded medical students concerning generalist practice. Limited funds provided over a sufficient period of time can induce schools to undertake significant curricular change.

Curriculum↗
PubMed2001

Handedness, language lateralisation and anatomical asymmetry in schizophrenia: meta-analysis.

BACKGROUND: Cerebral lateralisation appears to be decreased in schizophrenia. Results of studies investigating this, however, are equivocal. AIMS: To review quantitatively the literature on decreased lateralisation in schizophrenia. METHOD: Meta-analyses were conducted on 19 studies on handedness, 10 dichotic listening studies and 39 studies investigating anatomical asymmetry in schizophrenia. RESULTS: The prevalence of mixed- and left-handedness ('non-right-handedness') was significantly higher in patients with schizophrenia as compared to healthy controls, and also as compared to psychiatric controls. The analysis of dichotic listening studies revealed no significant difference in lateralisation in schizophrenia. However, when analysis was restricted to studies using consonant-vowel or fused word tasks, significantly decreased lateralisation in schizophrenia emerged. Asymmetry of the planum temporale and the Sylvian fissure was significantly decreased in schizophrenia, while asymmetry of the temporal horn of the lateral ventricle was not. CONCLUSION: Strong evidence is provided for decreased cerebral lateralisation in schizophrenia.

Brain↗
PubMed2001

Incidence of psychotic disorders in immigrant groups to The Netherlands.

BACKGROUND: Previous reports on the incidence of schizophrenia in immigrant groups to The Netherlands were based on hospital data. AIMS: To compare the incidence of psychotic disorders in the immigrant groups to that in natives. METHOD: Two-year first-contact incidence study in The Hague. RESULTS: The risks of schizophrenia, schizophreniform or schizoaffective disorder (DSM-IV criteria) were increased for subjects born in Morocco (gender and age-adjusted relative risk=4.5; 95% Cl 1.4-8.5), Surinam (relative risk=3.2; 1.8-5.7), The Netherlands Antilles (relative risk=2.9; 0.9-9.5) and other non-Western countries (relative risk=2.4; 1.3-4.7). This risk was also increased for Moroccans (relative risk=8.0; 2.6-24.5) and Surinamese (relative risk=5.5; 2.5-11.9) of the second generation. The risks for Turkish immigrants, first or second generation, and for immigrants from Western countries were not significantly increased. CONCLUSIONS: This study indicates that the incidence of schizophrenia is increased in several, but not all, immigrant groups to The Netherlands. It is possible that factors associated with a process of rapid westernisation precipitate schizophrenia in people who are genetically at risk.

Adult↗
PubMed2000

Seasonality of schizophrenia and stillbirths in The Netherlands.

Studies from Denmark and the USA have reported a strong correlation between the seasonal pattern for stillbirths and the seasonal birth pattern for people who develop schizophrenia. It has been suggested that the correlation could be caused by a common seasonal factor (e. g. intra-uterine infections during the third trimester of pregnancy), which produces death in some fetuses and nonfatal brain changes in others, changes that are manifested in later life as schizophrenia. The aims of our study were (i) to assess the seasonal patterns for stillbirths and for pre-schizophrenic births in The Netherlands and (ii) to examine their relationship. The Dutch psychiatric registry provided data on all Dutch-born subjects who had been hospitalized at least once with a diagnosis of schizophrenia in the period 1970-1994. We selected data on patients born in the period 1926-1970 (n=29891). The government provided monthly numbers of live births and stillbirths in the latter period. Seasonality of birth was examined using Poisson regression analysis. The risk of an admission for schizophrenia was highest for people born in the months of May and June and lowest for those born in August and September. When the risk for subjects born in June was compared with the risk for subjects born in September, the Relative Risk was 1.14 [95% confidence interval (CI): 1.07 to 1.22]. The seasonal pattern of stillbirths was different, in that it showed a peak in the month of January. The low, however, as in schizophrenia, occurred in the months of August and September. The two seasonal patterns were found to be weakly correlated: Spearman's rank correlation coefficient rho=0.41 (95% CI: -0.22 to 0.80). This was the largest European study on birth seasonality in schizophrenia. The hypothesis that a common factor is responsible for a seasonal excess of stillbirths and for a seasonal birth excess of people who develop schizophrenia was not supported. The possibility remains, however, that a common factor explains seasonal (birth rate) deficits in these disorders.

Birth Rate↗
PubMed2000

Feasibility and review of anomalous X-ray diffraction at long wavelengths in materials research and protein crystallography.

The feasibility and a review of progress in the long-wavelengths anomalous dispersion technique is given in the context of the development of beamline ID1 of the ESRF for such studies. First experiments on this beamline and their analyses are described. The first study reports on the use of uranium which exhibits an unusually strong anomalous dispersion at its M(V) absorption edge (lambda(M(V)) = 3.5 A). The anomalous scattering amplitude of uranium with 110 anomalous electrons exceeds the resonance scattering of other strong anomalous scatterers like that of the rare earth ions by a factor of four. The resulting exceptional phasing power of uranium is most attractive in protein crystallography using the MAD method. The anomalous dispersion of a uranium derivative of asparaginyl-tRNA synthetase (hexagonal, a = 124.4 A, c = 123.4 A) has been measured at three wavelengths near the M(V) edge using beamline ID1 of the ESRF. The present set-up allowed the measurement of 10% of the possible reflections at a resolution of 8 A. This is mainly due to the low sensitivity of the CCD camera. The second study, involving DAFS experiments at wavelengths near the K-absorption edge of chlorine (lambda(K) = 4.4 A), reports the use of salt crystals which give rise to much stronger intensities of diffraction peaks than those of protein crystals. In the case of a crystal of pentamethylammonium undecachlorodibismuthate (PMACB, orthorhombic, a = 13.00 A, b = 14.038 A, c = 15.45 A), all reflections within the resolution range from 6.4 A to 3.5 A and the total scan width of 24 degrees were collected. The crystalline structure of PMACB implies two chemically distinct states of the Cl atom. Consequently, different dispersions near the K-edge of chlorine are expected. The dispersion of the intensity of five Bragg peaks of the PMACB crystal has been measured at 30 wavelengths. The relative success of these preliminary experiments with X-rays of long wavelength shows that the measurement of anomalous X-ray diffraction at wavelengths beyond 3 A is feasible. Starting from the experience gained in these experiments, an increased efficiency of the instrument ID1 by two to three orders of magnitude will be achieved in this wavelength range. A comparison with different techniques of anomalous diffraction which rely on the use of argon/ethane-filled multiwire chambers and image plates as detectors for wavelengths near the K-edge of sulfur and phosphorus is also given.

Journal Article↗