IL1RN genotype as a risk factor for joint pain in hereditary haemochromatosis?
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Biomedical subjects
Publications and source records attributed to S R Wilson.
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Subarachnoid haemorrhage is a common neurological emergency, which carries a high morbidity and mortality. It is usually caused by rupture of an intracerebral aneurysm or, less commonly, an arteriovenous malformation. Although most patients present to a non-neurosurgical hospital, they often require urgent neurosurgical or neuroradiological intervention. Whilst awaiting transfer to a neurological centre, active management of the patient must be instituted. This should include confirmation of the diagnosis with CT imaging, lumbar puncture or both, and recognition of the complications of subarachnoid haemorrhage, which include hydrocephalus, further haemorrhage and cerebral vasospasm. Medical management is directed towards maintaining adequate cerebral perfusion pressure whilst avoiding large increases in arterial blood pressure. Nimodipine therapy must be started early in an attempt to prevent cerebral vasospasm. The treatment options available at the neurological centre include surgical treatment or endovascular obliteration of the aneurysm or arteriovenous malformation.
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) profoundly affects the quality of patients' lives. A systematic review was performed to evaluate critically the published literature and to examine what is known about health-related quality of life (HRQL) in patients with IPF. METHODS: The MEDLINE, EMBASE, Health and Psychosocial Instruments, and Cochrane Library databases were searched to 1 April 2004. Abstracts and bibliographies of published articles were scanned and contact was made with investigators. Included studies analysed HRQL (or quality of life) in at least 10 patients with IPF. Two reviewers independently selected studies, evaluated their quality according to predetermined criteria, and abstracted data on study design, patients' demographic and clinical characteristics, and quality of life outcome measures. RESULTS: Seven studies met the inclusion criteria. The studies enrolled 512 patients with IPF and used three different instruments to measure HRQL. All studies had important limitations in methodological quality; none measured longitudinal changes in HRQL over time. Patients reported substantially impaired HRQL, especially in domains that measured physical health and level of independence. Patients with IPF appear to have similar impairments in HRQL to those with chronic obstructive pulmonary disease. Measures of dyspnoea were moderately correlated with scores from domains that measured physical health (R2 = 0.03-0.66) and energy/fatigue/pep (R2 = 0.19-0.55), but measures of pulmonary function and gas exchange did not correlate as strongly with these and other domains. CONCLUSION: Studies of HRQL in patients with IPF suggest that, in addition to the obvious effect on physical health, general health, energy level, respiratory symptoms, and level of independence are also impaired. Variability in HRQL among patients is not fully explained by measures of dyspnoea or pulmonary function, suggesting that HRQL measures provide unique information. More research is needed to identify or design appropriate measurement instruments for patients with IPF and to examine changes in HRQL over time or in response to specific treatments.
We have previously reported strong evidence for linkage between IBD1 and Crohn's disease (CD) in Australian Crohn's disease families. Three risk alleles for Crohn's disease, (Arg702Trp (C/T), Gly908Arg (G/C) and 980fs981 (-/C), were recently identified in the CARD15/NOD2 gene on chromosome 16, implicating this as the IBD1 locus. Using a novel diagnostic PCR-RFLP, we have examined the frequency of these alleles in 205 multiplex IBD families, 107 sporadic Crohn's disease cases and 409 normal individuals. We demonstrate that the three risk alleles are more frequent in Crohn's disease, than in controls, with allelic frequencies of 0.11, 0.02 and 0.07 respectively. Heterozygosity for individual variants conferred a three-fold increase in risk for Crohn's disease while substantially higher risks were associated with being homozygous or compound heterozygous. Despite a significantly lower population allele frequency for the frameshift mutation than reported by other groups, we see a similar contribution by this allele to the risk of developing Crohn's disease. While the three risk alleles influence susceptibility to Crohn's disease in Australia, we show that these alleles do not fully explain the linkage evidence and suggest that there are very likely additional IBD1 susceptibility alleles yet to be described in Australian CD at the NOD2 locus. We also show a second linkage peak in Australian CD that provides some support for a second disease susceptibility locus on chromosome 16.
Tumors of the perianal area of dogs are common and include multiple tumor types. Whereas perianal adenomas occur often, adenocarcinomas of the apocrine glands of the anal sac occur less frequently. A review of the literature revealed no reports of squamous cell carcinomas arising from the epithelial lining of the anal sac. Squamous cell carcinomas originating from the lining of the anal sac were diagnosed in five dogs. Microscopically, the tumors consisted of variably sized invasive nests and cords of epithelial cells displaying squamous differentiation. Four of the five dogs were euthanatized because of problems associated with local infiltration by the tumors. In the fifth dog, there was no evidence of tumor 7 months after surgical removal, but further follow up was not available.
Lamb parasitism and performance were compared on three pasture treatments: browntop/white clover, Yorkshire fog/white clover, and ryegrass/white clover swards maintained at a sward height of 5cm in each of two years by using continuous variable stocking management. In year 1, lamb performance (both suppressively drenched (SD) and trigger drenched (TD)) was similar on ryegrass and browntop swards but was poorer (P<0.05) on Yorkshire fog swards. In year 2, lamb performance (both SD and TD) was markedly better on ryegrass than on Yorkshire fog or browntop swards. This coincided with an increase in white clover content in the ryegrass/white clover swards and a decrease in white clover content in the browntop/white clover swards. Lamb performance was related to the white clover content of the swards (R2=85.4, P<0.001 and R2=77.5, P<0.001 for SD lambs and TD lambs, respectively). Differences among pasture treatments in faecal egg count (FEC) of TD lambs were greater in year 2 than in year 1 when no significant pasture effects were observed. In year 2, FEC was lowest in lambs which grazed ryegrass/white clover, intermediate in those which grazed Yorkshire fog/white clover and highest in lambs which grazed browntop/white clover, despite herbage allowance (kg herbage mass/kg lamb mass) being greater on the browntop/white clover and Yorkshire fog/white clover swards than the ryegrass/white clover swards. Circulating antibodies to gastrointestinal parasites were measured at the end of year 2. Antibody titres were highest (P<0.05) in the plasma of lambs which grazed ryegrass/white clover swards, and lowest in lambs which grazed browntop/white clover swards due to differences in levels of antibody to (P<0.05) Haemonchus contortus, Ostertagia circumcincta larvae and adults, but not Trichostrongylus colubriformis larvae or adults. These findings indicate that pasture composition, especially, the proportion of white clover, can help alleviate the production losses due to gastrointestinal parasitism. This information can provide a quick and readily adoptable practice for farmers who aim to reduce drench reliance and could become a key component of any integrated parasite control programme.
A series of models for the active site (H-cluster) of the iron-only hydrogenase enzymes (Fe-only H2-ases) were prepared. Treatment of MeCN solutions of Fe2(SR)2(CO)6 with 2 equiv of Et4NCN gave [Fe2(SR)2(CN)2(CO)4](2-) compounds. IR spectra of the dicyanides feature four nu(CO) bands between 1965 and 1870 cm(-1) and two nu(CN) bands at 2077 and 2033 cm(-1). For alkyl derivatives, both diequatorial and axial-equatorial isomers were observed by NMR analysis. Also prepared were a series of dithiolate derivatives (Et4N)2[Fe2(SR)2(CN)2(CO)4], where (SR)2 = S(CH2)2S, S(CH2)3S. Reaction of Et4NCN with Fe2(S-t-Bu)2(CO)6 gave initially [Fe2(S-t-Bu)2(CN)2(CO)4](2-), which comproportionated to give [Fe2(S-t-Bu)2(CN)(CO)5](-). The mechanism of the CN(-)-for-CO substitution was probed as follows: (i) excess CN(-) with a 1:1 mixture of Fe2(SMe)2(CO)6 and Fe2(SC6H4Me)2(CO)6 gave no mixed thiolates, (ii) treatment of Fe2(S2C3H6)(CO)6 with Me3NO followed by Et4NCN gave (Et4N)[Fe2(S2C3H6)(CN)(CO)5], which is a well-behaved salt, (iii) treatment of Fe2(S2C3H6)(CO)6 with Et4NCN in the presence of excess PMe3 gave (Et4N)[Fe2(S2C3H6)(CN)(CO)4(PMe3)] much more rapidly than the reaction of PMe3 with (Et4N)[Fe2(S2C3H6)(CN)(CO)5], and (iv) a competition experiment showed that Et4NCN reacts with Fe2(S2C3H6)(CO)6 more rapidly than with (Et4N)[Fe2(S2C3H6)(CN)(CO)5]. Salts of [Fe2(SR)2(CN)2(CO)4](2-) (for (SR)2 = (SMe)2 and S2C2H4) and the monocyanides [Fe2(S2C3H6)(CN)(CO)5](-) and [Fe2(S-t-Bu)2(CN)(CO)5](-) were characterized crystallographically; in each case, the Fe-CO distances were approximately 10% shorter than the Fe-CN distances. The oxidation potentials for Fe2(S2C3H6)(CO)4L2 become milder for L = CO, followed by MeNC, PMe3, and CN(-); the range is approximately 1.3 V. In water,oxidation of [Fe2(S2C3H6)(CN)2(CO)4](2-) occurs irreversibly at -0.12 V (Ag/AgCl) and is coupled to a second oxidation.
There is substantial interest in dyads in which C(60) is covalently linked to electron donors, such as porphyrins, which absorb light strongly in the visible region. We present here the details of the syntheses of such compounds, which can be broadly organized into categories depending upon the nature of the linker joining the two chromophores. The structural aspects of intramolecular electronic interaction that we have sought to explore have dictated the synthetic strategies employed to generate these classes of molecules. Flexible glycol linkers were used to allow close approach between the fullerene and porphyrin, facilitating through-space interactions. These linkers also allowed studies of the effects of metal cation complexation. Naphthalene and alkyne linkers were used to examine the possible effects a conjugated or aromatic linker might have on photophysical properties. Finally, steroids were used as linkers in dyads expected to possess a large distance between the two chromophores, in which only through-bond interactions between the fullerene and porphyrin should be possible.
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To prepare novel estrogen receptor (ER) ligands, we have developed a facile approach to substituted hexahydrochrysene and tetrahydrobenzo[a]fluorene systems. Substituents, including basic side chains, were added to these systems, and their binding affinity to ERalpha and ERbeta, and in some cases their transcriptional activity were evaluated.
The new anionic carbon sulfides C6S10(2-) and C12S16(2-) are described and crystallographically characterized. The C12S16(2-) anion consists of two C6S8 units connected by an exceptionally long (2.157(12) A) S-S bond. In solution, C12S16(2-) exists in equilibrium with the radical C6S8(-*). The equilibrium constant for radical formation (293 K, THF) is 1.2 x 10(-4) M, as determined by optical spectroscopy at varying concentrations. Radical formation occurs through scission of the S-S bond. On the basis of variable temperature EPR spectra, the thermodynamic parameters of this process are DeltaH = +51.5 +/- 0.5 kJ x mol(-1) and DeltaS = +110 +/- 3 J x mol(-1) x K(-1). C6S10(2-) is an oxidation product of C3S5(2-) and consists of two C3S5 units connected by an S-S bond. The S-S bond length (2.135(4) A) is long, and the CS-SC torsion angle is unusually acute (52.1 degrees ), which is attributed to an attractive interaction between C3S2 rings. The oxidation of (Me4N)2C3S5 occurs at -0.90 V vs Fc+/Fc in MeCN, being further oxidized at -0.22 V. The similarity of the cyclic voltammogram of (Me4N)2C6S10 to that of (Me4N)2C3S5 indicates that C6S10(2-) is the initial oxidation product of C3S5(2-).
BACKGROUND: Managed care is practiced in both traditional institutional health maintenance organization (HMO) settings and in a variety of complex and decentralized office-based arrangements. This study examines how practice setting affects physician perceptions of the quality of professional practice and patient care in a managed care environment. PARTICIPANTS AND METHODS: A survey was conducted in 1998 of 1081 physicians in San Mateo County, California, who practice in either a traditional staff group model HMO (SGM-HMO) (n = 113) or office-based independent practice (OBIP) (n = 250). Respondents were surveyed about current and past practice characteristics, income changes, current satisfaction with professional and patient care matters, utility of treatment guidelines and formularies, and general perceptions of managed care. Responses were compared between practice settings using bivariate comparisons and logistic regression analyses. RESULTS: Physicians in the SGM-HMO and those in OBIP reported similar hours worked per week, time spent with patients during office visits, and total patient encounters per week. Declining income was more frequent in OBIP (61% vs 47%) and relatively more substantial (27% with income declines >25% vs 4% in SGM-HMO). Adjusting for income changes, practice setting, years in practice, and sex, SGM-HMO physicians were significantly more satisfied with a variety of professional and quality of care issues (P<.001), viewed more favorably the utility of treatment guidelines and drug formularies (P<.001), and held more positive general perceptions of managed care (P<.001) than OBIP physicians. CONCLUSIONS: In a managed care environment, SGM-HMO physicians are significantly more satisfied with the quality of practice and patient care than physicians in OBIP. This study suggests that the myriad managed care contracts, formularies, and guidelines received by physicians in OBIPs may lead to more negative perceptions of the quality of professional practice and patient care.
C(60)-Fullerene monomalonate adducts inactivate selectively the neuronal nitric oxide synthase isoform in a manner completely preventable by the concurrent presence of superoxide dismutase and catalase. This inactivation is time-, fullerene concentration-, and turnover-dependent and is not reversible by dilution. The di(carboxypropan-3-ol)methano-[60]-fullerene (diol adduct) has no effect on NADPH consumption by nNOS as measured in the absence of arginine substrate, but dramatically increases NADPH consumption in the presence of arginine. This fullerene-enhanced NADPH consumption is linked to oxygen as electron acceptor and is accompanied by the increased production of hydrogen peroxide. These effects of fullerene monomalonate adducts are unique to the nNOS isoform and are not observed using either the iNOS or the eNOS isoform. The inhibitory effects of fullerene monomalonate adducts are unaltered and insurmountable by increased concentrations of arginine, tetrahydrobiopterin, or calmodulin. These observations indicate that fullerene monomalonate adducts uncouple in the presence of arginine the formation of reactive oxygen intermediates from NO production by nNOS. These reactive oxygen intermediates dissociate from the enzyme and, acting from solution, inactivate NOS NO forming activity.
This paper develops mathematical theory to determine the representativeness of clone libraries for various models, defined below in the text. In particular, the means and variances of fragment lengths and the mean of the length of a randomly selected fragment are determined, as well as the probability of the event that a particular base pair of a given double-stranded DNA sequence is clonable. Further, some results are given for partial digestion where the digest is stopped before all cuts are made. A summary is given comparing the main biological conclusions from assuming that the length of the genome is (effectively) infinite with the corresponding conclusions from the more realistic assumption that the genome is of finite length.
Most approaches to analysing complex genetic disorders are based on an underlying model that assumes that the probability of being affected is mainly due to the effect of a major, single disease locus. Where the penetrance (the conditional probability of being affected) is hypothesised to be influenced by known covariates, methods have been developed to accommodate these covariates appropriately in the analysis. Unexplained variation in the incomplete penetrance is then attributed to either unspecified environmental effects or to other genes of small effect that might act epistatically with the 'disease gene'. Recently, there have been some proposals to incorporate two (or more) possibly epistatic identified loci as major effects in the analysis. However, the effect of two (or more) major epistatic disease genes on the analysis of data that assumes a single 'disease gene', and so ignores any other major gene, does not seem to have been explored. This investigation is undertaken here for triad data consisting of affected singletons and their parents. Following development of a quite general underlying genetic model, a global approach to analysing two marker loci for triad data is developed. This approach is the appropriate one for such data where two, possibly epistatic, loci have been identified a priori. The motivation for the development of this methodology is to evaluate the possible effect a second epistatic disease locus might be having on the results for triad data collected and analysed in different population studies, where the underlying analysis is based on an underlying major, single disease locus model. It is shown that, dependent on the population parameters associated with the other unidentified major disease gene, results concerning the single 'disease gene' can vary markedly. So, finding that conclusions differ from study to study may be indicative of the 'disease gene' under investigation acting epistatically with other major disease genes.
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Liver mass evaluation includes two essential elements--lesion detection and lesion characterization. Both of these are greatly improved on sonography with the addition of contrast agents and the use of specialized imaging techniques, particularly pulse inversion imaging. Ultrasound contrast agents are comprised of tiny microbubbles of gas that interact with the ultrasound beam producing an enhancement of the Doppler signal from blood. Pulse inversion imaging allows preferential detection of the signal from the microbubble agents with suppression of the signal from background tissue. Two imaging techniques include a low mechanical index (MI) nondestructive method to show lesional vascularity and a high MI destructive mode that produces disruption of the bubbles in a single frame. The latter allows for quantitative assessment of the relative enhancement of a lesion as compared with the adjacent liver parenchyma, which is a reflection of the relative vascular volumes. Vascular imaging has shown characteristic and reproducible features of common liver masses, including hemangioma, focal nodular hyperplasia, hepatocellular carcinoma, and liver metastases. Delayed postvascular enhancement of the normal liver, a phenomenon that is unique to certain classes of microbubble contrast agents, allows detection of more and smaller malignant lesions than on baseline.