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Showing papers by "Medical Research Council published in 2000"


Journal ArticleDOI
TL;DR: How and why various modern computing concepts, such as object-orientation and run-time linking, feature in the software's design are discussed and how the framework may be extended.
Abstract: WinBUGS is a fully extensible modular framework for constructing and analysing Bayesian full probability models. Models may be specified either textually via the BUGS language or pictorially using a graphical interface called DoodleBUGS. WinBUGS processes the model specification and constructs an object-oriented representation of the model. The software offers a user-interface, based on dialogue boxes and menu commands, through which the model may then be analysed using Markov chain Monte Carlo techniques. In this paper we discuss how and why various modern computing concepts, such as object-orientation and run-time linking, feature in the software's design. We also discuss how the framework may be extended. It is possible to write specific applications that form an apparently seamless interface with WinBUGS for users with specialized requirements. It is also possible to interface with WinBUGS at a lower level by incorporating new object types that may be used by WinBUGS without knowledge of the modules in which they are implemented. Neither of these types of extension require access to, or even recompilation of, the WinBUGS source-code.

5,620 citations


Journal ArticleDOI
16 Sep 2000-BMJ
TL;DR: The design and execution of research required to address the additional problems resulting from evaluation of complex interventions, those “made up of various interconnecting parts,” are examined.
Abstract: Randomised controlled trials are widely accepted as the most reliable method of determining effectiveness, but most trials have evaluated the effects of a single intervention such as a drug. Recognition is increasing that other, non-pharmacological interventions should also be rigorously evaluated.1-3 This paper examines the design and execution of research required to address the additional problems resulting from evaluation of complex interventions—that is, those “made up of various interconnecting parts.”4 The issues dealt with are discussed in a longer Medical Research Council paper (www.mrc.ac.uk/complex_packages.html). We focus on randomised trials but believe that this approach could be adapted to other designs when they are more appropriate. #### Summary points Complex interventions are those that include several components The evaluation of complex interventions is difficult because of problems of developing, identifying, documenting, and reproducing the intervention A phased approach to the development and evaluation of complex interventions is proposed to help researchers define clearly where they are in the research process Evaluation of complex interventions requires use of qualitative and quantitative evidence There are specific difficulties in defining, developing, documenting, and reproducing complex interventions that are subject to more variation than a drug. A typical example would be the design of a trial to evaluate the benefits of specialist stroke units. Such a trial would have to consider the expertise of various health professionals as well as investigations, drugs, treatment guidelines, and arrangements for discharge and follow up. Stroke units may also vary in terms of organisation, management, and skill mix. The active components of the stroke unit may be difficult to specify, making it difficult to replicate the intervention. The box gives other examples of complex interventions. #### Examples of complex interventions Service delivery and organisation: Stroke units Hospital at home Interventions directed at health professionals' behaviour: Strategies for implementing guidelines Computerised decision support Community interventions: Community …

3,235 citations


Journal ArticleDOI

810 citations


Journal ArticleDOI
TL;DR: The nucleotide sequence of the entire coding region of the MC4R gene is determined in 243 subjects with severe, early-onset obesity, resulting in a syndrome of hyperphagic obesity in humans that can present with either dominant or recessive patterns of inheritance.
Abstract: Over 20 severely obese subjects in 11 independent kindreds have been reported to have pathogenic heterozygous mutations in the gene encoding the melanocortin 4 receptor (MC4R), making this the most common known monogenic cause of human obesity. To date, the detailed clinical phenotype of this dominantly inherited disorder has not been defined, and no homozygous subjects have been described. We determined the nucleotide sequence of the entire coding region of the MC4R gene in 243 subjects with severe, early-onset obesity. A novel two-base pair GT insertion in codon 279 was found in two unrelated subjects, and four novel missense mutations, N62S, R165Q, V253I, C271Y, and one mutation (T112M) reported previously were found in five subjects. N62S was found in homozygous form in five children with severe obesity from a consanguineous pedigree. All four heterozygous carriers were nonobese. Several features of the phenotype, e.g. hyperphagia, tendency toward tall stature, hyperinsulinemia, and preserved reproductive function, closely resemble those reported previously in Mc4r knock-out mice. In addition, a marked increase in bone mineral density was seen in all affected subjects. In transient transfection assays, the N62S mutant receptor showed a responsiveness to alphaMSH that was intermediate between the wild-type receptor and mutant receptors carrying nonsense and missense mutations associated with dominantly inherited obesity. Thus MC4R mutations result in a syndrome of hyperphagic obesity in humans that can present with either dominant or recessive patterns of inheritance.

767 citations


Journal ArticleDOI
TL;DR: A genome-wide, phenotype-driven screen for dominant mutations in the mouse is undertaken, which has led to a substantial increase in themouse mutant resource and represents a first step towards systematic studies of gene function in mammalian genetics.
Abstract: As the human genome project approaches completion, the challenge for mammalian geneticists is to develop approaches for the systematic determination of mammalian gene function. Mouse mutagenesis will be a key element of studies of gene function. Phenotype-driven approaches using the chemical mutagen ethylnitrosourea (ENU) represent a potentially efficient route for the generation of large numbers of mutant mice that can be screened for novel phenotypes. The advantage of this approach is that, in assessing gene function, no a priori assumptions are made about the genes involved in any pathway. Phenotype-driven mutagenesis is thus an effective method for the identification of novel genes and pathways. We have undertaken a genome-wide, phenotype-driven screen for dominant mutations in the mouse. We generated and screened over 26,000 mice, and recovered some 500 new mouse mutants. Our work, along with the programme reported in the accompanying paper, has led to a substantial increase in the mouse mutant resource and represents a first step towards systematic studies of gene function in mammalian genetics.

662 citations


Journal ArticleDOI
TL;DR: Two studies assessed the effects of a training procedure, derived from Duncan's theory of goal neglect, on disorganized behavior following TBI and provided both experimental and clinical support for the efficacy of GMT toward the treatment of executive functioning deficits that compromise independence in patients with brain damage.
Abstract: Two studies assessed the effects of a training procedure (Goal Management Training, GMT), derived from Duncan’s theory of goal neglect, on disorganized behavior following TBI. In Study 1, patients with traumatic brain injury (TBI) were randomly assigned to brief trials of GMT or motor skills training. GMT, but not motor skills training, was associated with significant gains on everyday paper-and-pencil tasks designed to mimic tasks that are problematic for patients with goal neglect. In Study 2, GMT was applied in a postencephalitic patient seeking to improve her meal-preparation abilities. Both naturalistic observation and self-report measures revealed improved meal preparation performance following GMT. These studies provide both experimental and clinical support for the efficacy of GMT toward the treatment of executive functioning deficits that compromise independence in patients with brain damage. (JINS, 2000, 6, 299‐312.)

592 citations


Journal ArticleDOI
TL;DR: It is concluded that MBL may be of importance in first-line immune defense against several important pathogens in immunocompromised children.
Abstract: Mannose-binding lectin (MBL) is a collagenous serum lectin believed to be of importance in innate immunity. Genetically determined low levels of the protein are known to predispose to infections. In this study the binding of purified MBL to pathogens isolated from immunocompromised children was investigated by flow cytometry. Diverse Candida species, Aspergillus fumigatus, Staphylococcus aureus, and beta-hemolytic group A streptococci exhibited strong binding of MBL, whereas Escherichia coli, Klebsiella species, and Haemophilus influenzae type b were characterized by heterogeneous binding patterns. In contrast, beta-hemolytic group B streptococci, Streptococcus pneumoniae, and Staphylococcus epidermidis showed low levels of binding. Bound MBL was able to promote C4 deposition in a concentration-dependent manner. We conclude that MBL may be of importance in first-line immune defense against several important pathogens.

575 citations


Journal ArticleDOI
02 Mar 2000-Nature
TL;DR: It is shown that cannabinoid (CB) receptor agonism quantitatively ameliorated both tremor and spasticity in diseased mice, providing a rationale for patients' indications of the therapeutic potential of cannabis in the control of the symptoms of multiple sclerosis.
Abstract: Chronic relapsing experimental allergic encephalomyelitis (CREAE) is an autoimmune model of multiple sclerosis1. Although both these diseases are typified by relapsing-remitting paralytic episodes, after CREAE induction by sensitization to myelin antigens1 Biozzi ABH mice also develop spasticity and tremor. These symptoms also occur during multiple sclerosis and are difficult to control. This has prompted some patients to find alternative medicines, and to perceive benefit from cannabis use2. Although this benefit has been backed up by small clinical studies, mainly with non-quantifiable outcomes3,4,5,6,7, the value of cannabis use in multiple sclerosis remains anecdotal. Here we show that cannabinoid (CB) receptor agonism using R(+)-WIN 55,212, Δ9-tetrahydrocannabinol, methanandamide and JWH-133 (ref. 8) quantitatively ameliorated both tremor and spasticity in diseased mice. The exacerbation of these signs after antagonism of the CB1 and CB2 receptors, notably the CB1 receptor, using SR141716A and SR144528 (ref. 8) indicate that the endogenous cannabinoid system may be tonically active in the control of tremor and spasticity. This provides a rationale for patients' indications of the therapeutic potential of cannabis in the control of the symptoms of multiple sclerosis2, and provides a means of evaluating more selective cannabinoids in the future.

556 citations


Journal ArticleDOI
TL;DR: Depression is common and persistent in lung cancer patients, especially those with more severe symptoms or functional limitations, and Psychologic screening and appropriate intervention is an essential part of palliative care.
Abstract: PURPOSE: To evaluate self-reported depression rates in patients with inoperable lung cancer and to explore demographic, clinical, and quality-of-life (QOL) factors associated with depression and thus identify patients at risk. PATIENTS AND METHODS: Nine hundred eighty-seven patients from three palliative treatment trials conducted by the Medical Research Council Lung Cancer Working Party formed the study sample. 526 patients (53%) had poor prognosis small-cell lung cancer (SCLC) and 461 patients (47%) had good prognosis non–small-cell lung cancer (NSCLC). Hospital Anxiety and Depression Scale data and QOL items from the Rotterdam Symptom Checklist were analyzed, together with relevant demographic and clinical factors. RESULTS: Depression was self-rated in 322 patients (33%) before treatment and persisted in more than 50% of patients. SCLC patients had a three-fold greater prevalence of case depression than those with NSCLC (25% v 9%; P < .0001). An increased rate for women was found for good performance s...

533 citations


Journal ArticleDOI
TL;DR: In every diagnostic group, a highly significant correlation was found between total tau and phospho-tau (Alzheimer's disease, r(2)=0.73; frontotemporal dementia, r (2)=0.42), suggesting that the degree of phosphorylation of CSF-t Tau changes in different clinical conditions.

474 citations


Journal ArticleDOI
TL;DR: The central stalk in ATP synthase is made of γ, δ and ɛ subunits in the mitochondrial enzyme, and with crystals of F1-ATPase inhibited with dicyclohexylcarbodiimide, the complete structure was revealed.
Abstract: The central stalk in ATP synthase, made of γ, δ and ɛ subunits in the mitochondrial enzyme, is the key rotary element in the enzyme's catalytic mechanism. The γ subunit penetrates the catalytic (αβ)3 domain and protrudes beneath it, interacting with a ring of c subunits in the membrane that drives rotation of the stalk during ATP synthesis. In other crystals of F1-ATPase, the protrusion was disordered, but with crystals of F1-ATPase inhibited with dicyclohexylcarbodiimide, the complete structure was revealed. The δ and ɛ subunits interact with a Rossmann fold in the γ subunit, forming a foot. In ATP synthase, this foot interacts with the c-ring and couples the transmembrane proton motive force to catalysis in the (αβ)3 domain.

Journal ArticleDOI
TL;DR: It is found that the only kin to improve the nutritional status of children significantly (apart from mothers) are maternal grandmothers, and that this is reflected in higher survival probabilities for children with living mothers and women, and in the presence of non–reproductive grandmothers.
Abstract: Hypotheses for the evolution of human female life-history characteristics have often focused on the social nature of human societies, which allows women to share the burden of childcare and provisioning amongst other members of their kin group. We test the hypothesis that child health and survival probabilities will be improved by the presence of kin using a longitudinal database from rural Gambia. We find that the only kin to improve the nutritional status of children significantly (apart from mothers) are maternal grandmothers, and that this is reflected in higher survival probabilities for children with living maternal grandmothers. There is also evidence that the reproductive status of the maternal grandmother influences child nutrition, with young children being taller in the presence of non-reproductive grandmothers than grandmothers who are still reproductively active. Paternal grandmothers and male kin, including fathers, have negligible impacts on the nutritional status and survival of children.


Journal ArticleDOI
TL;DR: The low sensitivity of HCV RNA soon after birth and the finding of a lower transmission rate after delivery by elective caesarean section suggest that HCV transmission occurs predominantly around the time of delivery.

Journal ArticleDOI
TL;DR: The agreement between the clinician-rated scale and the scale completed by a non-clinician was determined and both scales correlated significantly with each other, and with the neuropsychological and electrophysiological measures of fluctuation.
Abstract: Background The identification of fluctuating confusion is central to improving the differential diagnosis of the common dementias. Aims To determine the value of two rating scales to measure fluctuating confusion. Method The agreement between the clinician-rated scale and the scale completed by a non-clinician was determined. Correlations between the two scales were calculated; variability in attention was calculated on a computerised cognitive assessment and variability in delta rhythm on an electroencephalogram (EEG). Results The Clinician Assessment of Fluctuation and the computerised cognitive assessment were completed for 155 patients (61 Alzheimer's disease, 37 dementia with Lewy bodies, 22 vascular dementia, 35 elderly controls). A subgroup ( n =40) received a further evaluation using the One Day Fluctuation Assessment Scale and an EEG. The two scales correlated significantly with each other, and with the neuropsychological and electrophysiological measures of fluctuation. Conclusions Both scales are useful instruments for the clinical assessment of fluctuation in dementia.

Journal ArticleDOI
TL;DR: It is suggested that GABAA receptors cycle between the synaptic membrane and intracellular sites, and their association with AP2 followed by recruitment into clathrin-coated pits represents an important mechanism in the postsynaptic modulation of inhibitory synaptic transmission.
Abstract: Type A GABA receptors (GABA(A)) mediate the majority of fast synaptic inhibition in the brain and are believed to be predominantly composed of alpha, beta, and gamma subunits. Although changes in cell surface GABA(A) receptor number have been postulated to be of importance in modulating inhibitory synaptic transmission, little is currently known on the mechanism used by neurons to modify surface receptor levels at inhibitory synapses. To address this issue, we have studied the cell surface expression and maintenance of GABA(A) receptors. Here we show that constitutive internalization of GABA(A) receptors in hippocampal neurons and recombinant receptors expressed in A293 cells is mediated by clathrin-dependent endocytosis. Furthermore, we identify an interaction between the GABA(A) receptor beta and gamma subunits with the adaptin complex AP2, which is critical for the recruitment of integral membrane proteins into clathrin-coated pits. GABA(A) receptors also colocalize with AP2 in cultured hippocampal neurons. Finally, blocking clathrin-dependant endocytosis with a peptide that disrupts the association between amphiphysin and dynamin causes a large sustained increase in the amplitude of miniature IPSCs in cultured hippocampal neurons. These results suggest that GABA(A) receptors cycle between the synaptic membrane and intracellular sites, and their association with AP2 followed by recruitment into clathrin-coated pits represents an important mechanism in the postsynaptic modulation of inhibitory synaptic transmission.

Journal ArticleDOI
TL;DR: The data indicate that STN and GP activity is intimately related to cortical activity and hence the sleep–wake cycle; rhythmic oscillatory activity in the STN–GP network in disease states may be driven by the cortex; and activity of the STn– GP network is regulated in space in a complex manner.
Abstract: One of the functions of the excitatory subthalamic nucleus (STN) is to relay cortical activity to other basal ganglia structures. The response of the STN to cortical input is shaped by inhibition from the reciprocally connected globus pallidus (GP). To examine the activity in the STN–GP network in relation to cortical activity, we recorded single and multiple unit activity in STN and/or GP together with cortical electroencephalogram in anesthetized rats during various states of cortical activation. During cortical slow-wave activity (SWA), STN and GP neurons fired bursts of action potentials at frequencies that were similar to those of coincident slow (∼1 Hz) and spindle (7–14 Hz) cortical oscillations. Spontaneous or sensory-driven global activation was associated with a reduction of SWA and a shift in STN–GP activity from burst- to tonic- or irregular-firing. Rhythmic activity in STN and GP neurons was lost when the cortex was inactivated by spreading depression and did not resume until SWA had recovered. Although rhythmic STN–GP activity was correlated with SWA, the phase relationships of activities of neurons within the STN and GP and between the nuclei were variable. Even when neurons displayed synchronous bursting activity, correlations on the millisecond time scale, which might indicate shared synaptic input, were not observed. These data indicate that (1) STN and GP activity is intimately related to cortical activity and hence the sleep–wake cycle; (2) rhythmic oscillatory activity in the STN–GP network in disease states may be driven by the cortex; and (3) activity of the STN–GP network is regulated in space in a complex manner.

Journal ArticleDOI
TL;DR: During voluntary activity in humans, motor units are exposed to a number of descending drives that tend to synchronize motor unit activity at particular frequencies, and inadequate output from these nuclei leads to a disappearance of the beta and Piper drives to muscle.

Journal ArticleDOI
TL;DR: It is concluded that neonatal exposure of rats to low levels of estrogens can advance the first wave of spermatogenesis at puberty, although it is unclear whether this is due to direct effects of the estrogen or to associated elevation of FSH levels.
Abstract: This study investigated whether neonatal exposure of male rats to estrogenic compounds altered pubertal spermatogenesis (days 18 and 25) and whether the changes observed resulted in long-term changes in testis size, mating, or fertility (days 90-100). Rats were treated neonatally with a range of doses (0.01-10 microg) of diethylstilbestrol (DES; administered on alternate days from days 2-12), a high dose of octylphenol (OP; 2 mg administered daily from days 2-12) or bisphenol A (Bis-A; 0.5 mg administered daily from days 2-12), or vehicle, while maintained on a standard soy-containing diet. The effect on the same parameters of rearing control animals on a soy-free diet was also assessed as was the effect of administering such animals genistein (4 mg/kg/day daily from days 2-18). Testis weight, seminiferous tubule lumen formation, the germ cell apoptotic index (apoptotic/viable germ cell nuclear volume), and spermatocyte nuclear volume per unit Sertoli cell nuclear volume were used to characterize pubertal spermatogenesis. Compared with (soy-fed) controls, DES administration caused dose-dependent retardation of pubertal spermatogenesis on day 18, as evidenced by decreases in testis weight, lumen formation, and spermatocyte nuclear volume per unit Sertoli cell and elevation of the germ cell apoptotic index. However, the two lowest doses of DES (0.1 and 0.01 microg) significantly increased spermatocyte nuclear volume per unit Sertoli cell. Similarly, treatment with either OP or Bis-A significantly advanced this and some of the other aspects of pubertal spermatogenesis. Maintenance of control animals on a soy-free diet also significantly advanced lumen formation and spermatocyte nuclear volume per unit Sertoli cell compared with controls fed a soy-containing diet. Administration of genistein reversed the stimulatory effects of a soy-free diet and significantly retarded most measures of pubertal spermatogenesis. In general, plasma FSH levels in the treatment groups changed in parallel to the spermatogenic changes (reduced when pubertal spermatogenesis retarded, increased when pubertal spermatogenesis advanced). By day 25, although the changes in FSH levels largely persisted, all of the stimulatory effects on spermatogenesis seen on day 18 in the various treatment groups were no longer evident. In adulthood, testis weight was decreased dose dependently in rats treated neonatally with DES, but only the lowest dose group (0.01 microg) showed evidence of mating (3 of 6) and normal fertility (3 litters). Animals treated neonatally with OP or Bis-A had normal or increased (Bis-A) testis weights and exhibited reasonably normal mating/fertility. Animals fed a soy-free diet had significantly larger testes than controls fed a soy-containing diet, and this difference was confirmed in a much larger study of more than 24 litters, which also showed a significant decrease in plasma FSH levels and a significant increase in body weight in the males kept on a soy-free diet. Neonatal treatment with genistein did not alter adult testis weight, and although most males exhibited normal mating and fertility, a minority did not mate or were infertile. It is concluded that 1) neonatal exposure of rats to low levels of estrogens can advance the first wave of spermatogenesis at puberty, although it is unclear whether this is due to direct effects of the estrogen or to associated elevation of FSH levels; 2) the effect of high doses of OP and Bis-A on these processes is essentially benign; and 3) the presence or absence of soy or genistein in the diet has significant short-term (pubertal spermatogenesis) and long-term (body weight, testis size, FSH levels, and possibly mating) effects on males.

Journal ArticleDOI
TL;DR: The results indicate that genome-wide linkage analysis can contribute to the mapping and identification of major genes for multifactorial infectious diseases of humans.
Abstract: Human genetic variation is an important determinant of the outcome of infection with Mycobacterium tuberculosis. We have conducted a two-stage genome-wide linkage study to search for regions of the human genome containing tuberculosis-susceptibility genes. This approach uses sibpair families that contain two full siblings who have both been affected by clinical tuberculosis. For any chromosomal region containing a major tuberculosis-susceptibility gene, affected sibpairs inherit the same parental alleles more often than expected by chance. In the first round of the screen, 299 highly informative genetic markers, spanning the entire human genome, were typed in 92 sibpairs from The Gambia and South Africa. Seven chromosomal regions that showed provisional evidence of coinheritance with clinical tuberculosis were identified. To identify whether any of these regions contained a potential tuberculosis-susceptibility gene, 22 markers from these regions were genotyped in a second set of 81 sibpairs from the same countries. Markers on chromosomes 15q and Xq showed suggestive evidence of linkage (lod = 2.00 and 1.77, respectively) to tuberculosis. The potential identification of susceptibility loci on both chromosomes 15q and Xq was supported by an independent analysis designated common ancestry using microsatellite mapping. These results indicate that genome-wide linkage analysis can contribute to the mapping and identification of major genes for multifactorial infectious diseases of humans. An X chromosome susceptibility gene may contribute to the excess of males with tuberculosis observed in many different populations.

Journal ArticleDOI
TL;DR: The final tree obtained represents the most detailed view to date of phylogenetic relationships in any family of large-genome viruses.
Abstract: With the aim of deriving a definitive phylogenetic tree for as many mammalian and avian herpesvirus species as possible, alignments were made of amino acid sequences from eight conserved and ubiquitously present genes of herpesviruses, with 48 virus species each represented by at least one gene. Phylogenetic trees for both single-gene and concatenated alignments were evaluated thoroughly by maximum-likelihood methods, with each of the three herpesvirus subfamilies (the Alpha-, Beta-, and Gammaherpesvirinae) examined independently. Composite trees were constructed starting with the top-scoring tree based on the broadest set of genes and supplemented by addition of virus species from trees based on narrower gene sets, to give finally a 46-species tree; branching order for three regions within the tree remained unresolved. Sublineages of the Alpha- and Betaherpesvirinae showed extensive cospeciation with host lineages by criteria of congruence in branching patterns and consistency in extent of divergence. The Gammaherpesvirinae presented a more complex picture, with both higher and lower substitution rates in different sublineages. The final tree obtained represents the most detailed view to date of phylogenetic relationships in any family of large-genome viruses.

Patent
28 Nov 2000
TL;DR: In this article, the authors described methods for the production of anti-self antibodies and antibody fragments, being antibodies or fragments of a particular species of mammal which bind self antigens of that species.
Abstract: Methods are disclosed for the production of anti-self antibodies and antibody fragments, being antibodies or fragments of a particular species of mammal which bind self antigens of that species. Methods comprise providing a library of replicable genetic display packages (rgdps), such as filamentous phage, each rgdp displaying at its surface a member of a specific binding pair which is an antibody or antibody fragment, and each rgdp containing nucleic acid sequence derived from a species of mammal. The nucleic acid sequence in each rgdp encodes a polypeptide chain which is a component part of the sbp member displayed at the surface of that rgdp. Anti-self antibody fragments are selected by binding with a self antigen from the said species of mammal. The displayed antibody fragments may be scFv, Fd, Fab or any other fragment which has the capability of binding antigen. Nucleic acid libraries used may be derived from a rearranged V-gene sequences of unimmunised mammal. Synthetic or artificial libraries are described and shown to be useful.

Journal ArticleDOI
TL;DR: Immunolocalization of Suv39h2 protein during spermatogenesis indicates enriched distribution at the heterochromatin from the leptotene to the round sperMatid stage, suggesting an additional function of the Suv 39h2 HMTase in organizing meiotic heterochromeatin that may even impart an epigenetic imprint to the male germ line.
Abstract: Higher-order chromatin has been implicated in epigenetic gene control and in the functional organization of chromosomes. We have recently discovered mouse (Suv39h1) and human (SUV39H1) histone H3 lysine 9-selective methyltransferases (Suv39h HMTases) and shown that they modulate chromatin dynamics in somatic cells. We describe here the isolation, chromosomal assignment, and characterization of a second murine gene, Suv39h2. Like Suv39h1, Suv39h2 encodes an H3 HMTase that shares 59% identity with Suv39h1 but which differs by the presence of a highly basic N terminus. Using fluorescent in situ hybridization and haplotype analysis, the Suv39h2 locus was mapped to the subcentromeric region of mouse chromosome 2, whereas the Suv39h1 locus resides at the tip of the mouse X chromosome. Notably, although both Suv39h loci display overlapping expression profiles during mouse embryogenesis, Suv39h2 transcripts remain specifically expressed in adult testes. Immunolocalization of Suv39h2 protein during spermatogenesis indicates enriched distribution at the heterochromatin from the leptotene to the round spermatid stage. Moreover, Suv39h2 specifically accumulates with chromatin of the sex chromosomes (XY body) which undergo transcriptional silencing during the first meiotic prophase. These data are consistent with redundant enzymatic roles for Suv39h1 and Suv39h2 during mouse development and suggest an additional function of the Suv39h2 HMTase in organizing meiotic heterochromatin that may even impart an epigenetic imprint to the male germ line.

Journal ArticleDOI
TL;DR: The study of patients with negative symptoms provides opportunities for testing cognitive models of goal-directed behaviour, and eventually to map such models onto the neurobiology of both normal and abnormal behaviour.

Journal ArticleDOI
TL;DR: In this article, an electron density map of the F(1)-c(10) subcomplex has been provided for a glimpse of the motor in the membrane domain of the transmembrane proton motive force.

Journal ArticleDOI
TL;DR: Assessment of the daidzein and genistein content of fruits and nuts commonly eaten in Europe found thatCurrants and raisins were the richest sources of the isoflavones, containing 2,250 microg and 1,840 microg of the two is oflavones combined per kilogram of wet weight of food.
Abstract: Dietary phytoestrogens such as the isoflavones daidzein and genistein are thought to protect against chronic diseases that are common in Western societies, such as cancer, osteoporosis, and ischemic heart disease In addition, there are concerns regarding the deleterious effects of hormone-like compounds, especially with respect to the development of infants However, there is little information regarding the phytoestrogen content of foods, and therefore epidemiologic investigations of phytoestrogens are limited As part of a study quantifying the consumption of phytoestrogens, the objective of this work was to assess the daidzein and genistein content of fruits and nuts commonly eaten in Europe Eighty different fruits and nuts were sampled, prepared for eating, and freeze-dried Daidzein and genistein were extracted from the dried foods, and the two isoflavones were quantified after hydrolytic removal of any conjugated carbohydrate Completeness of extraction and any procedural losses of the isoflavones were accounted for using synthetic daidzin (7-O-glucosyl-4'-hydroxyisoflavone) and genistin (7-O-glucosyl-4'5-dihydroxyisoflavone) as internal standards Of the 80 foods assayed, 43 contained no detectable daidzein or genistein, at a limit of quantification of 1 microg/kg dry weight of food Nine foods contained more than 100 microg of the two isoflavones combined per kilogram wet weight, and 28 contained less than this amount Currants and raisins were the richest sources of the isoflavones, containing 2,250 microg and 1,840 microg of the two isoflavones combined per kilogram of wet weight of food Although fruits and nuts are not as rich in isoflavone phytoestrogens as are soy and other legumes, this is the first documentation of levels of daidzein and genistein occurring in these foods

Journal ArticleDOI
TL;DR: The data support a hypothesis where the pfmdr1 gene confers a true multidrug resistance phenotype which is lost by mutation, and an intragenic association was found between a polymorphism in the polyasparagine linker region of pfmDr1 and the tyr-86 allele, which may be due to genetic hitchhiking, indicative of recent selection by chloroquine.

Journal ArticleDOI
TL;DR: This work uses logistic regression modelling to determine approximate risk on a larger scale and employs geo-statistical approaches to improve prediction at a local level of malaria risk, using climatic, population and topographic variables as potential predictors.
Abstract: Background Good maps of malaria risk have long been recognized as an important tool for malaria control. The production of such maps relies on modelling to predict the risk for most of the map, with actual observations of malaria prevalence usually only known at a limited number of specific locations. Estimation is complicated by the fact that there is often local variation of risk that cannot be accounted for by the known covariates and because data points of measured malaria prevalence are not evenly or randomly spread across the area to be mapped. Method We describe, by way of an example, a simple two-stage procedure for producing maps of predicted risk: we use logistic regression modelling to determine approximate risk on a larger scale and we employ geo-statistical ('kriging') approaches to improve prediction at a local level. Malaria prevalence in children under 10 was modelled using climatic, population and topographic variables as potential predictors. After the regression analysis, spatial dependence of the model residuals was investigated. Kriging on the residuals was used to model local variation in malaria risk over and above that which is predicted by the regression model. Results The method is illustrated by a map showing the improvement of risk prediction brought about by the second stage. The advantages and shortcomings of this approach are discussed in the context of the need for further development of methodology and software.

Journal ArticleDOI
TL;DR: Standardized assessment methods demonstrate that fluctuating cognition is significantly more common and severe in DLB than in other major dementias, with important implications for the underlying causal mechanisms and for differential diagnosis.
Abstract: Background: Case reports and clinical observations suggest that fluctuating cognition (FC) is common in the major dementias, particularly dementia with Lewy bodies (DLB), where it is one of three core clinical diagnostic features Objectives: To examine the frequency, characteristics, and diagnostic utility of FC in dementia using clinical, attentional, and EEG markers Method:— A total of 155 subjects (61 with AD, 37 with DLB, 22 with vascular dementia [VaD], 35 elderly controls) received clinical evaluation for FC using a semiquantified measure applied by experienced clinicians and 90-second cognitive choice reaction time (CRT) and vigilance reaction time (VIGRT) trials Forty subjects also received an evaluation of mean EEG frequency across 90 seconds Results: Patients with DLB had a greater prevalence and severity of FC than did patients with AD or VaD rated using clinical, attentional, and EEG measures The 90-second cognitive and EEG trials demonstrated that FC occurs on a second-to-second basis in patients with DLB Patients with VaD had a higher prevalence of FC than did those with AD, although the profile of FC was different from that expressed by DLB cases Optimal cutoff values on the clinical scale achieved good discrimination between the dementia groups (sensitivity 81%, specificity 92%, DLB versus AD; sensitivity 81%, specificity 82%, DLB versus VaD; sensitivity 64%, specificity 77%, VaD versus AD) Conclusion: Standardized assessment methods demonstrate that FC is significantly more common and severe in DLB than in other major dementias The periodicity of FC is different in DLB and VaD cases, with important implications for the underlying causal mechanisms and for differential diagnosis

Journal ArticleDOI
TL;DR: The changing spectrum of bacteria and antibiotic susceptibility patterns in HIV-1-infected children requires a reevaluation of the empirical treatment of community-acquired severe LRTI in children from developing countries with a high prevalence of childhood HIV- 1 infection.
Abstract: To improve the management of lower respiratory tract infections (LRTI) in human immunodeficiency virus type 1 (HIV-1)-infected children, we assessed the burden of disease, clinical outcome and antibiotic susceptibility of bacteria causing severe community-acquired LRTI in children. A prospective, descriptive study was performed in the pediatric wards at a secondary and tertiary care hospital in South Africa. Urban black children aged 2-60 months admitted with severe acute LRTI from March 1997 through February 1998 were enrolled. HIV-1 infection was present in 45.1% of 1215 cases of severe LRTI. Bacteremia occurred in 14.9% of HIV-1-infected and in 6.5% of HIV-1-uninfected children (P<.00001). The estimated relative incidence of bacteremic severe LRTI in children aged from 2 to 24 months were greater in HIV-1-infected than in -uninfected children for Streptococcus pneumoniae (risk ratio [RR], 42.9; 95% confidence interval [CI], 20.7-90.2), Haemophilus influenzae type b (RR, 21.4; 95% CI, 9.4-48.4), Staphylococcus aureus (RR, 97.9; 95% CI, 11.4-838.2) and Escherichia coli (RR, 49.0; 95% CI, 15.4-156). Isolation of Mycobacterium tuberculosis was also more common in HIV-1-infected than in -uninfected children (RR, 22.5; 95% CI, 13.4-37.6). In HIV-1-infected children, 60% of S. aureus and 85.7% of E. coli isolates were resistant to methicillin and trimethoprim-sulfamethoxazole, respectively. The case-fatality rates among HIV-1-infected children was 13.1%, and among HIV-1-uninfected children, 2.1% (adjusted odds ratio [AOR]; 6.52, 95% CI, 3.53-12.05; P<.00001). The changing spectrum of bacteria and antibiotic susceptibility patterns in HIV-1-infected children requires a reevaluation of the empirical treatment of community-acquired severe LRTI in children from developing countries with a high prevalence of childhood HIV-1 infection.