Showing papers by "Charles University in Prague published in 2001"

Kirsten ras mutations in patients with colorectal cancer: the ‘RASCAL II’ study

Abstract: Researchers worldwide with information about the Kirsten ras (Ki-ras) tumour genotype and outcome of patients with colorectal cancer were invited to provide that data in a schematized format for inclusion in a collaborative database called RASCAL (The Kirsten ras incolorectal-cancer collaborative group). Our results from 2721 such patients have been presented previously and for the first time in any common cancer, showed conclusively that different gene mutations have different impacts on outcome, even when the mutations occur at the same site on the genome. To explore the effect of Ki-ras mutations at different stages of colorectal cancer, more patients were recruited to the database, which was reanalysed when information on 4268 patients from 42 centres in 21 countries had been entered. After predetermined exclusion criteria were applied, data on 3439 patients were entered into a multivariate analysis. This found that of the 12 possible mutations on codons 12 and 13 of Kirsten ras, only one mutation on codon 12, glycine to valine, found in 8.6% of all patients, had a statistically significant impact on failure-free survival (P=0.004, HR 1.3) and overall survival (P=0.008, HR 1.29). This mutation appeared to have a greater impact on outcome in Dukes' C cancers (failure-free survival, P=0.008, HR 1.5, overall survival P=0.02, HR 1.45) than in Dukes' B tumours (failure-free survival, P=0.46, HR 1.12, overall survival P=0.36, HR 1.15). Ki-ras mutations may occur early in the development of pre-cancerous adenomas in the colon and rectum. However, this collaborative study suggests that not only is the presence of a codon 12 glycine to valine mutation important for cancer progression but also that it may predispose to more aggressive biological behaviour in patients with advanced colorectal cancer. ⌐ 2001 Cancer Research Campaign.

Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4-year results from the MORE trial.

Abstract: Raloxifene, a selective estrogen receptor modulator approved for the prevention and treatment of postmenopausal osteoporosis, has shown a significant reduction in breast cancer incidence after 3 years in this placebo-controlled, randomized clinical trial in postmenopausal women with osteoporosis This article includes results from an additional annual mammogram at 4 years and represents 3,004 additional patient-years of follow-up in this trial Breast cancers were ascertained through annual screening mammograms and adjudicated by an independent oncology review board A total of 7,705 women were enrolled in the 4-year trial; 2,576 received placebo, 2,557 raloxifene 60mg/day, and 2,572 raloxifene 120mg/day Women were a mean of 665-years old at trial entry, 19 years postmenopause, and osteoporotic (low bone mineral density and/or prevalent vertebral fractures) As of 1 November 1999, 61 invasive breast cancers had been reported and were confirmed by the adjudication board, resulting in a 72% risk reduction with raloxifene (relative risk (RR) 028, 95% confidence interval (CI) 017, 046) These data indicate that 93 osteoporotic women would need to be treated with raloxifene for 4 years to prevent one case of invasive breast cancer Raloxifene reduced the risk of estrogen receptor-positive invasive breast cancer by 84% (RR 016, 95% CI 009, 030) Raloxifene was generally safe and well-tolerated, however, thromboembolic disease occurred more frequently with raloxifene compared with placebo (p=0003) We conclude that raloxifene continues to reduce the risk of breast cancer in women with osteoporosis after 4 years of treatment, through prevention of new cancers or suppression of subclinical tumors, or both Additional randomized clinical trials continue to evaluate this effect in postmenopausal women with osteoporosis, at risk for cardiovascular disease, and at high risk for breast cancer

Randomized controlled trial of intravenous immunoglobulin versus oral prednisolone in chronic inflammatory demyelinating polyradiculoneuropathy

Abstract: This multicenter, randomized, double-blind, crossover trial compared a six week course of oral prednisolone tapering from 60 mg to 10 mg daily with intravenous immunoglobulin (IVIg) 2.0 g/kg given over one to two days for treating chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Twenty-four of the thirty-two randomized patients completed both treatment periods. Both treatments produced significant improvements in the primary outcome measure, change in an 11-point disability scale two weeks after randomization. There was slightly, but not significantly, more improvement after IVIg than with prednisolone, the mean difference between the groups in change in disability grade being 0.16 (95% CI = -0.35 to 0.66). There were also slightly, but not significantly, greater improvements favoring IVIg in the secondary outcome measures: time to walk 10 meters after two weeks and improvement in disability grade after six weeks. Results may have been biased against IVIg by the eight patients who did not complete the second arm of the trial. A serious adverse event (psychosis) attributable to treatment occurred in one patient while on prednisolone and in none with IVIg.

Ab initio calculations of exchange interactions, spin-wave stiffness constants, and Curie temperatures of Fe, Co, and Ni

Abstract: We have calculated Heisenberg exchange parameters for bcc Fe, fcc Co, and fcc Ni using the nonrelativistic spin-polarized Green-function technique within the tight-binding linear muffin-tin orbital method and by employing the magnetic force theorem to calculate total energy changes associated with a local rotation of magnetization directions. We have also determined spin-wave stiffness constants and found the dispersion curves for metals in question employing the Fourier transform of calculated Heisenberg exchange parameters. Detailed analysis of convergence properties of the underlying lattice sums was carried out and a regularization procedure for calculation of the spin-wave stiffness constant was suggested. Curie temperatures were calculated both in the mean-field approximation and within the Green-function random-phase approximation. The latter results were found to be in a better agreement with available experimental data.

Radiation hard silicon detectors—developments by the RD48 (ROSE) collaboration

Abstract: The RD48 (ROSE) collaboration has succeeded to develop radiation hard silicon detectors, capable to withstand the harsh hadron fluences in the tracking areas of LHC experiments. In order to reach this objective, a defect engineering technique was employed resulting in the development of Oxygen enriched FZ silicon (DOFZ), ensuring the necessary O-enrichment of about 2×1017 O/cm3 in the normal detector processing. Systematic investigations have been carried out on various standard and oxygenated silicon diodes with neutron, proton and pion irradiation up to a fluence of 5×1014 cm−2 (1 MeV neutron equivalent). Major focus is on the changes of the effective doping concentration (depletion voltage). Other aspects (reverse current, charge collection) are covered too and the appreciable benefits obtained with DOFZ silicon in radiation tolerance for charged hadrons are outlined. The results are reliably described by the “Hamburg model”: its application to LHC experimental conditions is shown, demonstrating the superiority of the defect engineered silicon. Microscopic aspects of damage effects are also discussed, including differences due to charged and neutral hadron irradiation.

Carbon Paste Electrodes in Modern Electroanalysis

Abstract: Recent trends and advances in the electrochemistry with both unmodified and modified carbon paste electrodes are reviewed (247 refs.). Present day knowledge of their basic physico-chemical properties and characteristics is surveyed, including some specifics important in electrochemical measurements. Special attention is paid to the possibilities of carbon paste-based electrodes in electrochemical investigations and in modern electroanalysis of inorganic ions or molecules, organic substances, biologically important compounds, and pharmaceuticals.

Low cerebrospinal fluid hypocretin (orexin) and altered energy homeostasis in human narcolepsy

Abstract: Hypocretins (orexins) are hypothalamic neuropeptides involved in sleep and energy homeostasis. Hypocretin mutations produce narcolepsy in animal models. In humans, narcolepsy is rarely due to hypocretin mutations, but this system is deficient in the cerebrospinal fluid (CSF) and brain of a small number of patients. A recent study also indicates increased body mass index (BMI) in narcolepsy. The sensitivity of low CSF hypocretin was examined in 38 successive narcolepsy-cataplexy cases [36 human leukocyte antigen (HLA)-DQB1*0602-positive] and 34 matched controls (15 controls and 19 neurological patients). BMI and CSF leptin levels were also measured. Hypocretin-1 was measurable (169 to 376 pg/ml) in all controls. Levels were unaffected by freezing/thawing or prolonged storage and did not display any concentration gradient. Hypocretin-1 was dramatically decreased (<100 pg/ml) in 32 of 38 patients (all HLA-positive). Four patients had normal levels (2 HLA-negative). Two HLA-positive patients had high levels (609 and 637 pg/ml). CSF leptin and adjusted BMI were significantly higher in patients versus controls. We conclude that the hypocretin ligand is deficient in most cases of human narcolepsy, providing possible diagnostic applications. Increased BMI and leptin indicate altered energy homeostasis. Sleep and energy metabolism are likely to be functionally connected through the hypocretin system.

Allosteric interactions between GB1 and GB2 subunits are required for optimal GABAB receptor function

Abstract: Recent studies on G-protein-coupled receptors revealed that they can dimerize. However, the role of each subunit in the activation process remains unclear. The gamma-amino-n-butyric acid type B (GABA(B)) receptor is comprised of two subunits: GB1 and GB2. Both consist of an extracellular domain (ECD) and a heptahelical domain composed of seven transmembrane alpha-helices, loops and the C-terminus (HD). Whereas GB1 ECD plays a critical role in ligand binding, GB2 is required not only to target GB1 subunit to the cell surface but also for receptor activation. Here, by analysing chimeric GB subunits, we show that only GB2 HD contains the determinants required for G-protein signalling. However, the HD of GB1 improves coupling efficacy. Conversely, although GB1 ECD is sufficient to bind GABA(B) ligands, the ECD of GB2 increases the agonist affinity on GB1, and is necessary for agonist activation of the receptor. These data indicate that multiple allosteric interactions between the two subunits are required for wild-type functioning of the GABA(B) receptor and highlight further the importance of the dimerization process in GPCR activation.

Construction and bootstrap analysis of DNA fingerprinting-based phylogenetic trees with the freeware program FreeTree : application to trichomonad parasites

Abstract: The Win95/98/NT program FreeTree for computation of distance matrices and construction of phylogenetic or phenetic trees on the basis of random amplified polymorphic DNA (RAPD), RFLP and allozyme data is presented. In contrast to other similar software, the program FreeTree (available at http://www.natur.cuni.cz/~flegr/programs/freetree or http://ijs.sgmjournals.org/content/vol51/issue3/) can also assess the robustness of the tree topology by bootstrap, jackknife or operational taxonomic unit-jackknife analysis. Moreover, the program can be also used for the analysis of data obtained in several independent experiments performed with non-identical subsets of taxa. The function of the program was demonstrated by an analysis of RAPD data from 42 strains of 10 species of trichomonads. On the phylogenetic tree constructed using FreeTree, the high bootstrap values and short terminal branches for the Tritrichomonas foetus/suis 14-strain branch suggested relatively recent and probably clonal radiation of this species. At the same time, the relatively lower bootstrap values and long terminal branches for the Trichomonas vaginalis 20-strain branch suggested more ancient radiation of this species and the possible existence of genetic recombination (sexual reproduction) in this human pathogen. The low bootstrap values and the star-like topology of the whole Trichomonadidae tree confirm that the RAPD method is not suitable for phylogenetic analysis of protozoa at the level of higher taxa. It is proposed that the repeated bootstrap analysis should be an obligatory part of any RAPD study. It makes it possible to assess the reliability of the tree obtained and to adjust the amount of collected data (the number of random primers) to the amount of phylogenetic signals in the RAPD data of the taxon analysed. The FreeTree program makes such analysis possible.

Oxidative stress, metabolism of ethanol and alcohol-related diseases.

Abstract: Alcohol-induced oxidative stress is linked to the metabolism of ethanol. Three metabolic pathways of ethanol have been described in the human body so far. They involve the following enzymes: alcohol dehydrogenase, microsomal ethanol oxidation system (MEOS) and catalase. Each of these pathways could produce free radicals which affect the antioxidant system. Ethanol per se, hyperlactacidemia and elevated NADH increase xanthine oxidase activity, which results in the production of superoxide. Lipid peroxidation and superoxide production correlate with the amount of cytochrome P450 2E1. MEOS aggravates the oxidative stress directly as well as indirectly by impairing the defense systems. Hydroxyethyl radicals are probably involved in the alkylation of hepatic proteins. Nitric oxide (NO) is one of the key factors contributing to the vessel wall homeostasis, an important mediator of the vascular tone and neuronal transduction, and has cytotoxic effects. Stable metabolites — nitrites and nitrates — were increased in alcoholics (34.3±2.6 vs. 22.7±1.2 µmol/l, p<0.001). High NO concentration could be discussed for its excitotoxicity and may be linked to cytotoxicity in neurons, glia and myelin. Formation of NO has been linked to an increased preference for and tolerance to alcohol in recent studies. Increased NO biosynthesis also via inducible NO synthase (NOS, chronic stimulation) may contribute to platelet and endothelial dysfunctions. Comparison of chronically ethanol-fed rats and controls demonstrates that exposure to ethanol causes a decrease in NADPH diaphorase activity (neuronal NOS) in neurons and fibers of the cerebellar cortex and superior colliculus (stratum griseum superficiale and intermedium) in rats. These changes in the highly organized structure contribute to the motor disturbances, which are associated with alcohol abuse. Antiphospholipid antibodies (APA) in alcoholic patients seem to reflect membrane lesions, impairment of immunological reactivity, liver disease progression, and they correlate significantly with the disease severity. The low-density lipoprotein (LDL) oxidation is supposed to be one of the most important pathogenic mechanisms of atherogenesis, and antibodies against oxidized LDL (oxLDL) are some kind of epiphenomenon of this process. We studied IgG oxLDL and four APA (anticardiolipin, antiphosphatidylserine, antiphosphatidylethanolamine and antiphosphatidylcholine antibodies). The IgG oxLDL (406.4±52.5 vs. 499.9±52.5 mU/ml) was not affected in alcoholic patients, but oxLDL was higher (71.6±4.1 vs. 44.2±2.7 µmol/l, p<0.001). The prevalence of studied APA in alcoholics with mildly affected liver function was higher than in controls, but not significantly. On the contrary, changes of autoantibodies to IgG oxLDL revealed a wide range of IgG oxLDL titers in a healthy population. These parameters do not appear to be very promising for the evaluation of the risk of atherosclerosis. Free radicals increase the oxidative modification of LDL. This is one of the most important mechanisms, which increases cardiovascular risk in chronic alcoholic patients. Important enzymatic antioxidant systems — superoxide dismutase and glutathione peroxidase — are decreased in alcoholics. We did not find any changes of serum retinol and tocopherol concentrations in alcoholics, and blood and plasma selenium and copper levels were unchanged as well. Only the zinc concentration was decreased in plasma. It could be related to the impairment of the immune system in alcoholics. Measurement of these parameters in blood compartments does not seem to indicate a possible organ, e.g. liver deficiency.

Synchronization as adjustment of information rates: detection from bivariate time series.

Abstract: An information-theoretic approach for studying synchronization phenomena in experimental bivariate time series is presented. "Coarse-grained" information rates are introduced and their ability to indicate generalized synchronization as well as to establish a "direction of information flow" between coupled systems, i.e., to discern the driving from the driven (response) system, is demonstrated using numerically generated time series from unidirectionally coupled chaotic systems. The method introduced is then applied in a case study of electroencephalogram recordings of an epileptic patient. Synchronization events leading to seizures have been found on two levels of organization of brain tissues and "directions of information flow" among brain areas have been identified. This allows localization of the primary epileptogenic areas, also confirmed by magnetic resonance imaging and pasitron emission tomography scans.

Induction of cancer cell apoptosis by α-tocopheryl succinate: molecular pathways and structural requirements

Abstract: The vitamin E analog a-tocopheryl succinate (a-TOS) can induce apoptosis. We show that the proapoptotic activity of a-TOS in hematopoietic and cancer cell lines involves inhibition of protein kinase C (PKC), since phorbol myristyl acetate prevented a-TOS-triggered apoptosis. More selective effectors indicated that a-TOS reduced PKCa isotype activity by increasing protein phosphatase 2A (PP2A) activity. The role of PKCa inhibition in a-TOS-induced apoptosis was confirmed using antisense oligonucleotides or PKCa overexpression. Gain- or loss-of-function bcl-2 mutants implied modulation of bcl-2 activity by PKC/PP2A as a mitochondrial target of a-TOS-induced proapoptotic signals. Structural analogs revealed that a-tocopheryl and succinyl moieties are both required for maximizing these effects. In mice with colon cancer xenografts, a-TOS suppressed tumor growth by 80%. This epitomizes cancer cell killing by a pharmacologically relevant compound without known side effects.

Dielectric, infrared, and Raman response of undoped SrTiO 3 ceramics: Evidence of polar grain boundaries

Abstract: Thorough Raman and infrared (IR) reflectivity investigations of nominally pure ${\mathrm{SrTiO}}_{3}$ ceramics in the 10--300 K range have revealed a clear presence of the polar phase whose manifestation steeply increases on cooling. The Raman strengths of the Raman-forbidden IR modes are proportional to ${\ensuremath{\omega}}_{\mathrm{TO}1}^{\ensuremath{-}\ensuremath{\alpha}}(\ensuremath{\alpha}\ensuremath{\approx}1.6)$ where ${\ensuremath{\omega}}_{\mathrm{TO}1}$ is the polar soft mode frequency. No pronounced permittivity dispersion is observed below the soft mode frequency so that, as in single crystals, the static permittivity is essentially determined by the soft mode contribution. A theory is suggested which assumes a frozen dipole moment connected with the grain boundaries which induces the polar phase in the grain bulk in correlation with the bulk soft-mode frequency. This stiffens slightly the effective soft mode response and reduces the low-temperature permittivity compared to that of single crystals. Moreover, the polar soft mode strongly couples to the ${E}_{g}$ component of the structural soft doublet showing that the polar axis is perpendicular to the tetragonal axis below the structural transition which is shifted to 132 K in our ceramics. Whereas the ${\mathrm{TiO}}_{6}$ octahedra tilt (primary order parameter) below the structural transition corresponds to that in single crystals, much smaller ${A}_{1g}\ensuremath{-}{E}_{g}$ splitting of the structural soft doublet shows that the tetragonal deformation (secondary order parameter) is nearly 10 times smaller, apparently due to the grain volume clamping in ceramics.

Complexity of Coloring Graphs without Forbidden Induced Subgraphs

Abstract: We give a complete characterization of parameter graphs H for which the problem of coloring H-free graphs is polynomial and for which it is NP-complete. We further initiate a study of this problem for two forbidden subgraphs.

The wind in confined thermal convection

Abstract: A large-scale circulation velocity, often called the ‘wind’, has been observed in turbulent convection in the Rayleigh–Benard apparatus, which is a closed box with a heated bottom wall. The wind survives even when the dynamical parameter, namely the Rayleigh number, is very large. Over a wide range of time scales greater than its characteristic turnover time, the wind velocity exhibits occasional and irregular reversals without a change in magnitude. We study this feature experimentally in an apparatus of aspect ratio unity, in which the highest attainable Rayleigh number is about 1016. A possible physical explanation is attempted.

Dynamical spreading of asteroid families by the Yarkovsky effect.

Abstract: The orbital distributions of prominent asteroid families are thought to be direct by-products of catastrophic disruption events among diameter D ≳ 100 kilometer bodies. Ejection velocities derived from studying observed families, however, are surprisingly high compared with results from impact experiments and simulations. One way to resolve this apparent contradiction is by assuming that D ≲ 20 kilometer family members, since their formation, have undergone semimajor axis drift by the thermal force called the Yarkovsky effect. Interactions between drifting family members and resonances can also produce unique eccentricity and/or inclination changes. Together, these outcomes help explain (i) why families are sharply bounded by nearby Kirkwood gaps, (ii) why some families have asymmetric shapes, and (iii) the curious presence of family members on short-lived orbits.

Sorbitol-fermenting Shiga toxin-producing Escherichia coli O157:H(-) strains: epidemiology, phenotypic and molecular characteristics, and microbiological diagnosis.

Abstract: The significance of Shiga toxin (Stx)-producing Escherichia coli (STEC) O157:H7 as the major cause of hemorrhagic colitis and the hemolytic-uremic syndrome (HUS) worldwide has been well established (for reviews, see references[21][1], [31][2], [41][3], and [60][4]). The recognition of this pathogen

Transgenic rescue of defective Cd36 ameliorates insulin resistance in spontaneously hypertensive rats.

Abstract: Spontaneously hypertensive rats (SHR) display several features of the human insulin-resistance syndromes. Cd36 deficiency is genetically linked to insulin resistance in SHR. We show that transgenic expression of Cd36 in SHR ameliorates insulin resistance and lowers serum fatty acids. Our results provide direct evidence that Cd36 deficiency can promote defective insulin action and disordered fatty-acid metabolism in spontaneous hypertension.

Investment, Credit Rationing, and the Soft Budget Constraint: Evidence from Czech Panel Data

Abstract: Strategic restructuring of firms through investment is key to a transition from plan to market. Using data on industrial firms in the Czech Republic during 1992-98, we find that (a) foreign owned companies invest the most and cooperatives the least, (b) private firms do not invest more than state-owned ones and (c) cooperatives and small firms are credit rationed. Given the large volume of non-performing bank loans to firms and the high rate of investment of large state owned and private firms, our findings also suggest that these firms operate under a soft budget constraint. Estimates of a dynamic model, together with the support for the neoclassical model, suggest that firms started to behave consistently with profit-maximization.

Decrease of psychomotor performance in subjects with latent 'asymptomatic' toxoplasmosis.

Abstract: Toxoplasma gondii is known to induce specific behavioural changes in its intermediate hosts. This is usually considered to be an evolutionary adaptation aimed to increase the probability of transmission of the parasite into its definitive host, the cat, by predation. In rodents an increase of reaction time as well as many other specific behavioural patterns have been observed. Here we report the results of our double blind study showing the significantly longer reaction times of 60 subjects with latent toxoplasmosis in comparison with those of 56 controls. Moreover, the existence of a positive correlation between length of infection and mean reaction time suggested that slow and cumulative effects of latent toxoplasmosis rather than a one-step (and possibly transient) effect of acute toxoplasmosis disease are responsible for the decrease of psychomotor performance of infected subjects. To our knowledge, this is the first study confirming the existence of such parasite-induced changes in human behaviour that could be considered in evolutionary history of the human species as adaptive from the point of view of parasite transmission.

On embeddings between classical Lorentz spaces

Abstract: Let p ∈ (0, ∞) , let v be a weight on (0, ∞) and let Λp(v) be the classical Lorentz space, determiined by the norm ∥f∥Λp(v) := (∫∞0(f*(t))pv(t)dt) 1/p. When p ∈ (1, ∞), this space is known to be a Banach space if and only if v is non-increasing, while it is only equivalent to a Banach space if and only if Λp(v) = Γp(v), where ∥f∥Γp(v) := (∫∞0(f**(t))pv(t) t/p. We may thus conclude that, for p ∈ (1, ∞), the space Λp(v) is equivalent to a Banach space if and only if the norm of a function f in it can be expressed in terms of f**. We study the question whether an analogous assertion holds when p = 1. Motivated by this problem, we consider general embeddings between four types of classical and weak Lorentz spaces, namely, Λp(v), Λp,∞(v), Γp(v), Γp,∞(v), where Λp,∞(v) and Γp∞(v) are certain weak analogues of the spaces Λp(v) and Γp(v), respectively. We present a unified approach to these embeddings, based on rearrangement techniques. We survey all the known results and prove new ones. Our main results concern the embedding Γp,∞(v) → Λq(w) which had not been characterized so far. We apply our results to the characterization of associate spaces of classical and weak Lorentz spaces and we give a characterization of fundamental functions for which the endpoint Lorentz space and the endpoint Marcinkiewicz space coincide.

Pauwels' classification of femoral neck fractures: correct interpretation of the original.

Abstract: Pauwels' classification has been in use as a therapeutic guideline since 1935. Although its application is currently limited, it is still referred to and frequently misinterpreted by authors. The causes of this misinterpretation relate first of all to the degrees of the inclination of the fracture line in Degrees II and III of the classification. The correct values of Pauwels' classification are the following: Degree I, up to 30 degrees; Degree II, between 30 and 50 degrees; and Degree III, 50 degrees and more.

Prevalent vertebral deformity predicts incident hip though not distal forearm fracture: results from the European Prospective Osteoporosis Study.

Abstract: The presence of a vertebral deformity increases the risk of subsequent spinal deformities. The aim of this analysis was to determine whether the presence of vertebral deformity predicts incident hip and other limb fractures. Six thousand three hundred and forty-four men and 6788 women aged 50 years and over were recruited from population registers in 31 European centers and followed prospectively for a median of 3 years. All subjects had radiographs performed at baseline and the presence of vertebral deformity was assessed using established morphometric methods. Incident limb fractures which occurred during the follow- up period were ascertained by annual postal questionnaire and confirmed by radiographs, review of medical records and personal interview. During a total of 40348 person-years of follow-up, 138 men and 391 women sustained a limb fracture. Amongst the women, after adjustment for age, prevalent vertebral deformity was a strong predictor of incident hip fracture, (rate ratio (RR) = 4.5; 95% CI 2.1-9.4) and a weak predictor of 'other' limb fractures (RR = 1.6; 95% CI 1.1-2.4), though not distal forearm fracture (RR = 1.0; 95% CI 0.6-1.6). The predictive risk increased with increasing number of prevalent deformities, particularly for subsequent hip fracture: for two or more deformities, RR = 7.2 (95% CI 3.0-17.3). Amongst men, vertebral deformity was not associated with an increased risk of incident limb fracture though there was a nonsignificant trend toward an increased risk of hip fracture with increasing number of deformities. In summary, prevalent radiographic vertebral deformities in women are a strong predictor of hip fracture, and to a lesser extent humerus and 'other' limb fractures; however, they do not predict distal forearm fractures.

Functional magnetic resonance imaging during deep brain stimulation: a pilot study in four patients with Parkinson's disease.

Abstract: Functional magnetic resonance imaging (fMRI) was performed in patients with Parkinson's disease during deep brain stimulation of the subthalamic nucleus (three patients) and during deep brain stimulation of the ventral intermedius nucleus of the thalamus (one patient). All showed an increase in blood oxygenation level-dependent signal in the subcortical regions ipsilateral to the stimulated nucleus. This effect cannot be simply explained by a mechanism of depolarization blockade; rather, it is caused by overstimulation of the target nucleus, resulting in the suppression of its spontaneous activity. We confirm that fMRI during deep brain stimulation is a safe method with considerable potential for elucidating the functional connectivity of the stimulated nuclei.

Mitochondrial Type Iron-Sulfur Cluster Assembly in the Amitochondriate Eukaryotes Trichomonas vaginalis and Giardia intestinalis, as Indicated by the Phylogeny of IscS

Abstract: Pyridoxal-5'-phosphate-dependent cysteine desulfurase (IscS) is an essential enzyme in the assembly of FeS clusters in bacteria as well as in the mitochondria of eukaryotes. Although FeS proteins are particularly important for the energy metabolism of amitochondrial anaerobic eukaryotes, there is no information about FeS cluster formation in these organisms. We identified and sequenced two IscS homologs of Trichomonas vaginalis (TviscS-1 and TviscS-2) and one of Giardia intestinalis (GiiscS). TviscS-1, TviscS-2, and GiiscS possess the typical conserved regions implicated in cysteine desulfurase activity. N-termini of TviscS-1 and TviscS-2 possess eight amino acid extensions, which resemble the N-terminal presequences that target proteins to hydrogenosomes in trichomonads. No presequence was evident in GiiscS from Giardia, an organism that apparently lacks hydrogenosmes or mitochondria. Phylogenetic analysis showed a close relationship among all eukaryotic IscS genes including those of amitochondriates. IscS of proteobacteria formed a sister group to the eukaryotic clade, suggesting that isc-related genes were present in the proteobacterial endosymbiotic ancestor of mitochondria and hydrogenosomes. NifS genes of nitrogen-fixing bacteria, which are IscS homologs required for specific formation of FeS clusters in nitrogenase, formed a more distant group. The phylogeny indicates the presence of a common mechanism for FeS cluster formation in mitochondriates as well as in amitochondriate eukaryotes. Furthermore, the analyses support a common origin of Trichomonas hydrogenosomes and mitochondria, as well as secondary loss of mitochondrion/hydrogenosome-like organelles in Giardia.

Mapping susceptibility genes for bipolar disorder: a pharmacogenetic approach based on excellent response to lithium.

Abstract: Genetic mapping studies in bipolar disorder (BD) have been hampered by the unclear boundaries of the phenotypic spectrum, and possibly, by the complexity of the underlying genetic mechanisms, and heterogeneity. Among the suggested approaches to circumvent these problems, a pharmacogenetic strategy has been increasingly proposed. Several studies have indicated that patients with BD who respond well to lithium prophylaxis constitute a biologically distinct subgroup. In this study we have conducted a complete genome scan using 378 markers spaced at an average distance of 10 cM in 31 families ascertained through excellent lithium responders. Response to lithium was evaluated prospectively with an average follow-up of 12 years. Evidence for linkage was found with a locus on chromosome 15q14 (ACTC, lod score = 3.46, locus-specific P-value = 0.000014) and suggestive results were observed for another marker on chromosome 7q11.2 (D7S1816, lod score = 2.68, locus-specific P-value = 0.00011). Other interesting findings were obtained with markers on chromosomes 6 and 22, namely D6S1050 (lod score = 2.0, locus-specific P-value = 0.00004) and D22S420 (lod score = 1.91). Nonparametric linkage analysis provided additional support for the role of these loci. Further analyses of these results suggested that the locus on chromosome 15q14 may be implicated in the etiology of BD, whereas the 7q11.2 locus may be relevant for lithium response. In conclusion, our results provide original evidence suggesting that loci on 15q14 and 7q11.2 may be implicated in the pathogenesis of BD responsive to lithium.