Catalytic antibodies in clinical and experimental pathology: human and mouse models

Most of the data accumulated through studies on natural catalytic autoantibodies indicate that production scales up markedly in pathological abnormalities. We have previously described an increased level of DNA-hydrolyzing autoantibodies in the sera of patients with various autoimmune disorders [systemic lupus erythematosus (SLE), rheumatoid arthritis, scleroderma], HIV infection and lymphoproliferative diseases accompanied by autoimmune manifestations. In the present study, we show that an increased level of catalytic activity of autoantibodies can be observed in the sera of autoimmune mice, thus providing a fundamental insight into the medical relevance of abzymes. Polyclonal autoantibodies purified from sera of NZB/W, MRL-lpr/lpr and SJL/J mice show proteolytic and DNA-hydrolyzing activities, as opposed to those harvested from non-autoimmune BALB/c mice. The expressiveness of the catalytic activity was strongly dependent on the age of the animal. The highest levels of catalytic activity were found in the sera of mice aged between 8 and 12 months; the lowest level was typical of younger animals whose age ranged from 6 to 8 weeks. Specific inhibition assays of the catalytic activities were performed to throw light on the nature of the abzyme activity. Within a cohort of aging animals, a strong correlation between marked autoimmune abnormalities and levels of catalytic activities has been established. Nonimmunized SJL/J mice revealed specific immune responses to myelin basic protein (MBP), skeletal muscle myosin (skMyo) and cardiac myosin (Myo), and highly purified antibodies from their serum show specific proteolytic attack against the target antigens. This finding prompted us to undertake a more detailed study of specific antibody-mediated proteolysis in diseased humans. A targeted catalytic response was originally demonstrated against MBP and Myo in multiple sclerosis and myocarditis patients, respectively.     

Polyphenolic Profile of Larch Knotwood

Pharmaceutical Chemistry Journal - Studies of the polyphenol profile of knotwood from larch Larix dahurica Turcz. by HPLC-DAD/ESI-MS/MS found that knotwood differed from the butt-log portion by the...     

CO2 Methanation: Nickel–Alumina Catalyst Prepared by Solid-State Combustion

The development of solvent-free methods for the synthesis of catalysts is one of the main tasks of green chemistry. A nickel–alumina catalyst for CO₂ methanation was synthesized by solid-state combustion method using hexakis-(imidazole) nickel (II) nitrate complex. Using X-ray Powder Diffraction (XRD), Transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), and Hydrogen temperature-programmed reduction (H₂-TPR), it was shown that the synthesized catalyst is characterized by the localization of easily reduced nickel oxide on alumina surface. This provided low-temperature activation of the catalyst in the reaction mixture containing 4 vol% CO₂. In addition, the synthesized catalyst had higher activity in low-temperature CO₂ methanation compared to industrial NIAP-07-01 catalyst, which contained almost three times more hard-to-reduce nickel–aluminum spinel. Thus, the proposed approaches to the synthesis and activation of the catalyst make it possible to simplify the catalyst preparation procedure and to abandon the use of solvents, which must be disposed of later on.     

Cancer mortality among Moscow shoe workers exposed to chloroprene (Russia)

Objectives: To assess the risk of cancer among workers of a Moscow (Russia) shoe factory exposed to chloroprene (2-chloro-1,3-butadiene) (CP).Methods: This is a retrospective cohort mortality study among 5,185 shoe manufacturing workers employed between 1940 and 1976, and followed from 1979 through 1993. Exposure to CP was assessed by linking the job history with industrial hygiene data. We calculated standardized mortality ratios (SMR) using the Moscow population as reference, and conducted an internal comparison analysis based on Poisson regression modeling.Results: For the entire cohort, all-cause mortality was close to expectation and all-cancer mortality was increased. There was an increase in the mortality from liver cancer (SMR=2.4, 95 percent confidence interval [CI]=1.1-4.3), kidney cancer (SMR=1.8, CI=0.9-3.4), and leukemia (SMR=1.9, CI=1.0-3.3). Mortality from liver cancer and leukemia was associated with various indicators of CP exposure. A similar, although less consistent, pattern was found for kidney cancer mortality; while for the remaining neoplasms, no association was suggested with CP exposure.Conclusions: The association between CP exposure and risk of leukemia may be due to concomitant exposure to benzene. The results for liver cancer point towards a carcinogenic effect of CP.     

The effects of expressive writing on pain, depression and posttraumatic stress disorder symptoms in survivors of intimate partner violence

This study examined the effects of expressive writing on depression, posttraumatic stress disorder (PTSD) and pain symptoms among women who have survived intimate partner violence (IPV). Forty-seven women completed baseline and four-month follow-up assessments and were randomly assigned to four writing sessions of either expressive writing focused on traumatic life events or writing about a neutral topic. Main effects were not significant for changes in depression, pain or PTSD symptoms. However, among depressed women, those assigned to expressive writing showed a significantly greater drop in depression. For depressed women with IPV histories, expressive writing may lead to reduced depression.     

The safety of amoxicillin/clavulanic acid and cefuroxime during lactation

Breast-feeding is considered the gold standard for infant nutrition. In spite of statements about the safe use of drugs in lactation by the American Academy of Pediatrics, medical professionals remain confused regarding the management of drug therapy in nursing mothers, and this can lead to suboptimal prescribing and poor compliance. The aim of our study was to evaluate the safety of 2 of the newer antibiotics, amoxicillin/clavulanic acid and cefuroxime, during lactation. Breast-feeding women who called a drug consultation center to obtain information about the potential risks of amoxicillin/clavulanic acid (67 women) and cefuroxime (38 women) were prospectively recruited. As a control group, women who were treated with antibiotics known to be safe during lactation were recruited: amoxicillin (n = 40) for the amoxicillin/clavulanic acid group and cephalexin (n = 11) for the cefuroxime group. Women in the control group were matched for indication for antibiotic therapy, duration of treatment, and maternal age. Participants were interviewed after treatment termination regarding adverse reactions during therapy. In the amoxicillin/clavulanic acid group, 15 infants (22.3%) had adverse effects, and the rate increased with dosage (P = 0.0139). This was significantly higher than the amoxicillin group, where 3 infants (7.5%) had adverse effects (P = 0.046, relative risk (RR) = 2.99, 95% confidence interval (CI) 0.92-9.68). However, there were no significant differences between rates of specific events. The rate of adverse effects in the cefuroxime group (2.6%) was not significantly different from that in controls (9%) (P = 0.58, OR = 0.92, 95% CI 0.94-1.06). All adverse effects were minor, self-limiting, and did not necessitate interruption of breast-feeding. Our data suggest that amoxicillin/clavulanic acid and cefuroxime may be safe during lactation. Larger studies are needed to confirm these findings.     

Clinical pharmacokinetics of trospium chloride

Trospium chloride, a quaternary amine with anticholinergic properties, is used for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency and urinary frequency. The pharmacokinetics of trospium chloride have been investigated in healthy volunteers, in patients with renal and hepatic impairment, and in those with symptoms of overactive bladder, after oral, intravenous and intravesical administration.After oral administration, absorption of the hydrophilic trospium chloride is slow and incomplete. Peak plasma concentrations (Cmax) of approximately 4 ng/mL are reached 4-5 hours after administration of a 20 mg immediate-release preparation. The mean bioavailability is approximately 10% and decreases by concomitant food intake (to a mean of 26% of the fasting area under the plasma concentration-time curve [AUC]). Trospium chloride displays dose proportional increases in AUC and Cmax after a single dose within the clinically relevant dose range (20-60 mg). The mean volume of distribution is approximately 350-800 L. The drug is minimally (mean approximately 10%) metabolised to spiroalcohol by hydrolysis, is 50% plasma protein bound and does not cross the blood-brain barrier. Urinary excretion of the parent compound plays a major role in the disposition of the drug, with a mean renal clearance of 29 L/h (accounting for approximately 70% of total clearance) and a mean elimination half-life ranging from 10 to 20 hours. Elimination of the drug is slowed in patients with renal insufficiency, and population pharmacokinetic modelling has demonstrated that drug clearance is correlated with serum creatinine concentration. Thus, dose reduction is needed in patients with severe renal impairment (i.e. creatinine clearance < 30 mL/min).To date, no clinically relevant pharmacokinetic drug-drug interactions have been identified; the drug does not bind to any of the drug metabolising cytochrome P450 enzymes.The pharmacokinetics of the drug are compatible with twice-daily administration. A once-daily schedule may also be appropriate, but this regimen needs formal clinical evaluation.     

Decreased survival of B cells of HIV-viremic patients mediated by altered expression of receptors of the TNF superfamily

Human immunodeficiency virus (HIV) infection leads to numerous perturbations of B cells through mechanisms that remain elusive. We performed DNA microarray, phenotypic, and functional analyses in an effort to elucidate mechanisms of B cell perturbation associated with ongoing HIV replication. 42 genes were up-regulated in B cells of HIV-viremic patients when compared with HIV-aviremic and HIV-negative patients, the majority of which were interferon (IFN)-stimulated or associated with terminal differentiation. Flow cytometry confirmed these increases and indicated that CD21(low) B cells, enhanced in HIV-viremic patients, were largely responsible for the changes. Increased expression of the tumor necrosis factor (TNF) superfamily (TNFSF) receptor CD95 correlated with increased susceptibility to CD95-mediated apoptosis of CD21(low) B cells, which, in turn, correlated with HIV plasma viremia. Increased expression of BCMA, a weak TNFSF receptor for B lymphocyte stimulator (BLyS), on CD21(low) B cells was associated with a concomitant reduction in the expression of the more potent BLyS receptor, BAFF-R, that resulted in reduced BLyS binding and BLyS-mediated survival. These findings demonstrate that altered expression of genes associated with IFN stimulation and terminal differentiation in B cells of HIV-viremic patients lead to an increased propensity to cell death, which may have substantial deleterious effects on B cell responsiveness to antigenic stimulation.