More than skin deep: atherosclerosis as a systemic manifestation of psoriasis.

There is now growing evidence that psoriasis, like other inflammatory diseases such as rheumatoid arthritis and systemic lupus erythematosus, is a systemic disorder that is associated with enhanced atherosclerosis and risk of coronary artery disease. Here we summarize the available epidemiological evidence for this association and analyse pathogenic features that are common to psoriasis and atherosclerosis. Further prospective studies are urgently needed to extend knowledge of the risk of cardiovascular morbidity and mortality in patients with psoriasis and to confirm the degree to which treatment of psoriasis reduces this risk. Nevertheless, existing data are sufficient to indicate that severe psoriasis should be more widely recognized as a potential risk factor for cardiovascular disease and should be considered with the established factors when formulating strategies for the management of cardiovascular risk.

Cytokinin activity: localization in transfer RNA preparations.

Transfer RNA from yeast, liver, and Escherichia coli has cytokinin activity in the tobacco callus bioassay, whereas ribosomal RNA from yeast is inactive. In contrast to fractions of yeast transfer RNA rich in serine acceptor and cytokinin activity, preparations (70 to 90 percent pure) of arginine transfer RNA(2), glycine transfer RNA, phenylalanine transfer RNA, and valine transfer RNA(1) and of highly purified alanine transfer RNA from yeast were inactive at concentrations of 20 to 2500 micrograms per liter. One molecule of 6-(gamma,gamma-dimethylallylamino) purine per 20 molecules of yeast tRNA would account for the observed cytokinin activity. The number of major molecular species contributing to cytokinin activity of transfer RNA, therefore, must be small.

Cytokinin from soluble RNA of Escherichia coli: 6-(3-methyl-2-butenylamino)-2-methylthio-9-beta-D-ribofuranosylpurine.

We have isolated a compound responsible for the cytokinin activity of soluble RNA from Escherichia coli. The structure, indicated as 6-(3-methyl-2-butenylamino)-2-methylthio-9-beta-D-ribofuranosylpurine, C(16)H(23)N(5)0(4)S, on the basis of low-and high-reso!ution mass spectrometry, was established by unequivocal synthesis. The mass spectra, chromatographic behavior, and ultraviolet spectra of the compounds from natural and synthetic sources were identical.

Cytokinin of wheat germ transfer RNA: 6-(4-hydroxy-3-methyl-2-butenylamino)-2-methylthio-9-beta-D-ribofuranosylpurine.

A new modified nucleoside is responsible, in part, for the cytokinin activity of transfer RNA from wheat germ. The structure as judged by mass spec-trometry is 6-(4-hydroxy-3-methyl-2-butenylamino)-2-methylthio-9-beta-D-ribofuran-osylpurine. Unequivocal synthesis afforded material having ultraviolet, mass spectral, and chromatographic properties identical with those of the natural product.

Polymorphisms within the adenosine receptor 2a gene are associated with adverse events in RA patients treated with MTX.

OBJECTIVE: To examine the role of adenosine receptor 2a gene (ADORA2a) polymorphisms on outcome of MTX treatment in RA. METHODS: Subjects included 309 RA patients with a defined response to MTX. Patients were included if they were (i) good responders (n = 147) (ESR <20 for >6/12 on stable dose of MTX) (ii) inefficacy failures (n = 101) (physician statement and failure to reduce ESR/CRP by 20%) or (iii) adverse event (AE) failures (n = 61) (verified by medical record review). AEs were sub-divided into gastrointestinal (GI) (n = 24), abnormal LFTs (n = 20) or other (n = 17). 8 single nucleotide polymorphisms (SNPs) within ADORA2a were genotyped using the Sequenom MALDI-TOF platform. RESULTS: Five SNPs within ADORA2a were associated with stopping MTX for AEs (OR 2.1-3.07, P < 0.05 for all). Analysis by AE type showed that the association was specific for GI toxicity. No association was observed between ADORA2a and inefficacy outcomes. CONCLUSION: Genetic variation within ADORA2a is significantly associated with AEs on MTX, specifically GI AEs. Knowledge of the ADORA2a genotype may help to improve identification of patients at high risk of GI toxicity with MTX.

Phase modulation failsafe system for multi-kJ lasers based on optical heterodyne detection.

Amplification of the transverse scattered component of stimulated Brillouin scattering (SBS) can contribute to optical damage in the large aperture optics of multi-kJ lasers. Because increased laser bandwidth from optical phase modulation (PM) can suppress SBS, high energy laser amplifiers are injected with PM light. Phase modulation distributes the single-frequency spectrum of a master oscillator laser among individual PM sidebands, so a sufficiently high modulation index ß can maintain the fluence for all spectral components below the SBS threshold. To avoid injection of single frequency light in the event of a PM failure, a high-speed PM failsafe system (PMFS) must be employed. Because PM is easily converted to AM, essentially all PM failsafes detect AM, with the one described here employing a novel configuration where optical heterodyne detection converts PM to AM, followed by passive AM power detection. Although the PMFS is currently configured for continuous monitoring, it can also detect PM for pulse durations ≥2 ns and could be modified to accommodate shorter pulses. This PMFS was deployed on the Z-Beamlet Laser (ZBL) at Sandia National Laboratories, as required by an energy upgrade to support programs at Sandia's Z Facility such as magnetized liner inertial fusion. Depending on the origin of a PM failure, the PMFS responds in as little as 7 ns. In the event of an instantaneous failure during initiation of a laser shot, this response time translates to a 30-50 ns margin of safety by blocking a pulse from leaving ZBL's regenerative amplifier, which prevents injection of single frequency light into the main amplification chain. The performance of the PMFS, without the need for operator interaction, conforms to the principles of engineered safety.

Vitamin D deficiency is associated with anxiety and depression in fibromyalgia.

Fibromyalgia is a complex problem in which symptoms of anxiety and depression feature prominently. Low levels of vitamin D have been frequently reported in fibromyalgia, but no relationship was demonstrated with anxiety and depression. Seventy-five Caucasian patients who fulfilled the ACR criteria for fibromyalgia had serum vitamin D levels measured and completed the Fibromyalgia Impact Questionnaire (FIQ) and Hospital Anxiety and Depression Score (HADS). Deficient levels of vitamin D was found in 13.3% of the patients, while 56.0% had insufficient levels and 30.7% had normal levels. Patients with vitamin D deficiency (<25 nmol/l) had higher HADS [median, IQR, 31.0 (23.8-36.8] than patients with insufficient levels [25-50 nmol/l; HADS 22.5 (17.0-26.0)] or than patients with normal levels [50 nmol/l or greater; HADS 23.5 (19.0-27.5); Kruskal-Wallis ANOVA on ranks p<0.05]. There was no relationship with global measures of disease impact or musculoskeletal symptoms. Vitamin D deficiency is common in fibromyalgia and occurs more frequently in patients with anxiety and depression. The nature and direction of the causal relationship remains unclear, but there are definite implications for long-term bone health.

Cytokinin autonomy in tissue cultures of phaseolus: a genotype-specific and heritable trait.

Intra- and interspecific differences in cytokinin requirement were detected in callus cultures of Phaseolus vulgaris L. and P. lunatus L. Of the ten genotypes of P. vulgaris tested in the present study, one required cytokinin for callus growth, six exhibited some to moderate growth on cytokinin-free medium, and the remaining three grew uniformly in the absence of cytokinin. In contrast, six of the P. lunatus genotypes were strictly cytokinin-dependent, while four genotypes displayed irregular amount of callus growth on cytokinin-free medium. The genotype-specific behavior of Phaseolus callus tissues was independent of the tissue of origin and the time in culture. The inheritance of the cytokinin requirement of Phaseolus tissue cultures was studied in hybrid tissues resulting from crosses between a strictly cytokinin-dependent genotype (P.I. 200960) and two independent genotypes (cv. G 50 and P.I. 286303) of P. vulgaris. Fresh weights of hybrid tissues on cytokinin-free medium were intermediate between and significantly different from the parental tissues. No differences were found between reciprocal hybrids. These results suggest that cytokinin autonomy in tissue cultures of P. vulgaris is a genetic trait under nuclear control. Both parental and intermediate phenotypes were recovered in the F(2) progeny. The frequency distribution of cytokinin-dependent progeny in F(2) and backcross populations indicates that the cytokinin requirement of P. vulgaris callus tissue may be regulated by one set of alleles.

Distinctive effects of G-CSF, GM-CSF and TNFalpha on neutrophil apoptosis in systemic lupus erythematosus.

OBJECTIVE: To investigate the influence of culture with G-CSF GM-CSF and TNFalpha on neutrophil apoptosis, comparing neutrophils from SLE patients with rheumatoid arthritis (RA) patients and healthy control subjects. METHODS: Neutrophils were isolated from SLE (n= 10), RA (n= 10) and healthy control subjects (n= 10), and cultured with two different concentrations of G-CSF, GM-CSF and TNFalpha. Proportion of apoptotic neutrophils at T=0, T=2hrs and T=24hrs was measured using FITC-labelled annexinV and flow cytometry. RESULTS: Significantly more neutrophils were apoptotic at T=0 in the SLE subjects than in the other groups (median, range--Control 3.5% (0.3-7.9) SLE 9.5% (2.9-29.1) RA 3.0% (0.4-23.0) p<0.05). Following culture for 24 hours with 1ng/ml G-CSF the proportion of apoptotic neutrophils from SLE subjects was significantly increased (median, range = 51.6% (27.0-84.0) without G-CSF v 66.8% (31.8-89.2) with G-CSF p<0.05). This was not observed with RA or control subjects, in whom the trend was towards inhibition of apoptosis. Similar trends were seen with GM-CSF There was significant induction of apoptosis in SLE neutrophils after 2 hr culture with 1ng/ml TNFalpha (median, range = 2.3% (0.1-8.0) without TNFalpha v 5.2% (1.0-22.4) with TNFalpha). No significant change was seen in the other groups. There was an inverse correlation between total neutrophil count and the degree of induction of apoptosis by G-CSF and GM-CSF, determined at a range of time-points and cytokine concentrations CONCLUSIONS: Neutrophils from SLE patients display resistance to the apoptosis-inhibiting effects of G-CSF and possibly GM-CSF, and appear more susceptible to the apoptosis-inducing action of TNFalpha, the greatest resistance being observed in the more neutropenic patients.

Acquired dysfibrinogenaemia in liver disease.

Using a new and sensitive screening method, dysfibrinogenaemia (DF) was detected in 76% of patients with cirrhosis, 78% with chronic active liver disease and 86% with acute liver failure. The incidence was much lower in obstructive jaundice (8%) and miscellaneous liver disorders (4%). It is concluded that the fibrin monomer polymerisation (FMP) ratio test is a simple and sensitive test for the detection of DF, and is useful in the differential diagnosis of hepatocellular and obstructive jaundice. Hyperfibrinogenaemia, particularly in patients with obstructive jaundice, may explain the high incidence of abnormal thrombin and Reptilase clotting times despite normal FMP ratios. Dysfibrinogenaemia dose not appear to be related to the degree of liver function impairment, but may be associated with regeneration of hepatic tissue.

Systemic vasculitis and aneurysm formation in the Wiskott-Aldrich syndrome.

A 24 year old male who suffered from the Wiskott-Aldrich syndrome developed intra-abdominal bleeding on two occasions. Radiological investigations showed aneurysmal dilatation of branches of the hepatic and superior mesenteric arteries. The second abdominal bleed necessitated laparotomy and the bleeding was localised to the kidneys. Right nephrectomy was performed and histological examination showed a necrotising vasculitis, mainly involving medium and small sized renal blood vessels. Steroids, immunosuppressive treatment, and control of blood pressure resulted in resolution of the vasculitic process and prevented further haemorrhage. Vasculitis and aneurysm formation are rarely described complications of Wiskott-Aldrich syndrome and may account for the life threatening haemorrhage which occurs in this condition.

Reflex tracheal contraction evoked in dogs by bronchodilator prostaglandins E2 and I2.

Bronchodilator prostaglandins E2 and I2 may cause airway irritation and bronchoconstriction in human subjects. These experiments were designed to test the hypothesis that this paradoxical bronchoconstriction is a vagal reflex triggered by stimulation of airway afferents. We recorded smooth muscle tension in an innervated upper tracheal segment in anesthetized dogs and injected prostaglandins into the general circulation or into a bronchial artery or administered them as aerosol to the lungs. Prostaglandins usually caused tracheal contraction, which survived vagal cooling to 5-7 degrees C but was abolished at 0 degrees C. Vagally mediated tracheal contraction was also evoked when prostacyclin was injected into the pulmonary circulation of dogs whose pulmonary and systemic circulations were independently pump perfused. Recordings of afferent vagal impulses indicated that bronchial arterial injection of prostaglandins stimulated bronchial C-fibers; aerosols of prostaglandin stimulated pulmonary and bronchial C-fibers and C-fibers in extrapulmonary airways. We postulate that in susceptible human subjects concentrations of these prostaglandins too low to have direct bronchodilator effects may cause reflex bronchoconstriction by stimulating afferent vagal C-fibers in the lower airways.

Influence of pH on the release of propranolol hydrochloride from matrices containing hydroxypropylmethylcellulose K4M and carbopol 974.

The dissolution of propranolol hydrochloride from matrices containing hydroxypropylmethylcellulose K4M (HPMC K4M) and carbopol 974 has been investigated using 0.1 M hydrochloric acid or phosphate buffer at pH 4.5 or pH 7.5. In 0.1 M hydrochloric acid, HPMC K4M predominantly controlled release since carbopol has a low solubility at this pH. As the pH increased, the carbopol became increasingly ionized and interacted with propranolol hydrochloride to form an insoluble complex which retarded the release of the drug. In addition, the nature of the interaction between carbopol 974 and HPMC K4M altered. DSC and viscometric studies indicated that the two polymers contributed synergistically to the gel network at pH 7.5. Thus at pH 7.5 polymers contributed to matrix integrity and to the control of drug release.

Poly-(D,L-lactic acid) microspheres incorporating histological dyes for intra-pulmonary histopathological investigations.

Polylactic acid (PLA) microspheres incorporating fluorescein as a histological marker have been prepared and used as a model for the testing of inhaled PLA microspheres (2-5 microns) in the lung. PLA microspheres (20 mg) were delivered to rabbits in the form of a saline nebulization. The distribution pattern within the pulmonary system showed that the fluorescein-labelled microspheres were distributed about the four lobes in discrete groups. The comparative numbers of these groups showed a trend towards a reduced concentration in the lower lobes. Subsequent histological examination revealed that the microsphere-treated lungs had been significantly damaged after 24 h. Histological damage was assessed in terms of pulmonary haemorrhage, eosinophilia and neutrophil infiltration.

The role of glutathione in the toxicity of xenobiotic compounds: metabolic activation of 1,2-dibromoethane by glutathione.

Unstable metabolites may arise during the metabolism of xenobiotic compounds with enzyme systems other than the cytochrome P-450 system. This depends on the enzyme system involved and the structure of the xenobiotic compound being metabolized. Normally detoxifying pathways may transform selected chemicals into toxic metabolites. In our laboratory we have demonstrated that DBE is metabolized by both cytochrome P-450 and GSH S-transferases. Although the cytochrome P-450 metabolite is reactive and will covalently bind to protein and nucleic acid to some extent, and the GSH S-transferase system conjugates it and under conditions of low DBE exposure is able to detoxify it. In contrast, GSH S-transferase catalyzes the direct conjugation of GSH with DBE. This can result in formation of a reactive intermediate that preferentially binds to nucleic acids and is responsible for the DNA damage observed following DBE exposure. The selective toxicity of this xenobiotic compound may be due to the preponderance of activating GSH conjugating enzymes in the extrahepatic organs. However, this difference alone does not appear sufficient to explain the selection of extrahepatic organs as sites of DBE-induced toxicity.

Identification of minor C18 triene and conjugated diene isomers in hydrogenated soybean oil and margarine by GC-MI-FT-IR spectroscopy.

Vegetable oils are partially hydrogenated in order to produce palatable products of suitable plasticity. The constituents of these new dietary products are complex mixtures of fatty acid isomers with different nutritional properties. A rapid method is described for separating and identifying fatty acid methyl ester (FAME) isomers of linolenic (octadecatrienoic, 18:3) acid and of conjugated octadecadienoic (18:2) acid, minor species found in hydrogenated soybean oil and margarine, by capillary gas chromatography-matrix isolation-Fourier transform-infrared (GC-MI-FT-IR) spectroscopy. FAMEs of 18:3 acid isomers in margarine, soybean oil hydrogenated in our laboratory, and isomerized linolenic acid were identified by this method, and MI-FT-IR spectra of FAME geometric isomers of octadecatrienoic and conjugated octadecadienoic acids are reported for the first time. Five major C18 triene GC peaks are found in chromatograms of isomerized methyl linolenate, representing species with tri-cis and tri-trans configurations and three species with cis-trans mixed configurations. FAME isomers with these configurations are also found for a hydrogenated soybean oil having an iodine value of 111. Methyl linolenate (tri-cis) is no longer found when soybean oil is further hydrogenated to an iodine value of 96. IR spectra characteristic of a tri-trans isomer are obtained for two test samples with iodine values of 111 and 96. Besides methyl linolenate, only isomers with a mono-trans di-cis configuration are found for the margarine analyzed. Conjugated cis-trans and trans-trans 18:2 FAME isomers are also found in all the hydrogenated soybean oil and margarine analyzed.

The use of the mini C-arm in the outpatient setting: evolving practice.

The mini C-arm image intensifier (mini C-arm) has now become an established diagnostic tool in the hand surgery outpatient department. This study reviews the use of the mini C-arm and formal radiographs (X-rays) in the outpatient hand surgery setting. X-rays provide a standard image whereas the mini C-arm can obtain non-standard images to aid diagnosis and treatment. The mini C-arm enables the clinician to obtain dynamic images and perform interventions such as manipulations or injections. The mini C-arm results in a significantly lower radiation exposure for the patients than a formal X-ray. Use of the mini C-arm may be cheaper, and can lead to a shorter outpatient visit with less travel between hospital departments.

Rheumatoid arthritis patients with active disease and no history of cardiac pathology have higher brain natriuretic peptide (BNP) levels than patients with inactive disease or healthy control subjects.

BACKGROUND: Rheumatoid arthritis (RA) is associated with increased incidence cardiac failure. It is yet unclear how much the increased incidence is secondary to ischaemic damage, or whether inflammatory cytokines might have a direct effect on the myocardium. OBJECTIVES: To establish if patients with active rheumatoid arthritis but no history of cardiac disease have higher serum levels of brain natriuretic peptide (BNP), than patients with less active RA, or disease-free controls. METHODS: 90 patients with RA and 31 healthy control subjects were recruited. Each was screened to exclude previous history of cardiac disease. RA disease activity was measured using the DAS28 assessment, and other demographic, physical and laboratory tests performed. Serum BNP levels were measured in all subjects. RESULTS: There was no difference in the age, percentage females or BMI between the RA and control subjects. Median BNP in the RA patients was 80.0 pg/ml (IQR 38.0-132.0) compared with 48.5 (26.0-86.0) in the control subjects (p=0.017). There was a significant correlation between DAS28 and serum BNP in the RA group, r=0.37, p<0.01. RA patients were divided into three groups according to DAS28 scores. Patients with very active disease (DAS28>5.1) had significantly higher BNP levels than patients with moderately active disease (3.2