Potential role of coenzyme Q10 in facilitating recovery from statin-induced rhabdomyolysis.

Rhabdomyolysis is a rare, but serious complication of statin therapy, and represents the most severe end of the spectrum of statin-induced myotoxicity. We report a case where coenzyme Q10 facilitated recovery from statin-induced rhabdomyolysis and acute renal failure, which had initially persisted despite statin cessation and haemodialysis. This observation is biologically plausible due to the recognised importance of coenzyme Q10 in mitochondrial bioenergetics within myocytes, and the fact that statins inhibit farnesyl pyrophosphate production, a biochemical step crucial for coenzyme Q10 synthesis. Coenzyme Q10 is generally well tolerated, and may potentially benefit patients with statin-induced rhabdomyolysis.

Transcription factors.

The regulation of gene expression by transcription factors is fundamental to the phenotype of all cells. The activated phenotype of cells engaged in inflammatory processes is characterized by induced expression of a diverse set of genes, including cytokines, enzymes and cell adhesion molecules. A relatively small number of inducible transcription factors, particularly NF-kappaB, AP-1, NFATs and STATs, are responsible for the expression of a wide variety of inflammatory phenotypic characteristics and therefore play a central role in the pathogenesis of rheumatic diseases. Each of these transcription factors can be modified by existing anti-rheumatic and anti-inflammatory drugs, although adverse effects and limited efficacy remain problems. The future development of therapeutic agents with specificity for transcription factors, especially NF-kappaB, might lead to safer and more effective treatment.

Carboxyfluorescein diacetate succinimidyl ester and the virgin lymphocyte: a marriage made in heaven.

Carboxyfluorescein diacetate succinimidyl ester (CFSE) labelling of naïve lymphocyte populations provides unique insights into the immune response. The clonal nature of immune responses, necessitating clonal expansion to achieve a sufficiently large number of Ag-reactive effector cells, combined with the dependence of lymphocyte differentiation on cell division, underlie the usefulness of CFSE in understanding the factors that regulate responses both in vitro and in vivo. We have combined CFSE labelling with Ag receptor transgenic models, using seven channel flow cytometry to track the correlation between cell division and a number of other parameters, such as surface expression of activation markers, cytokine receptors and homing receptors, cytokine production, cytotoxic activity and indicators of apoptosis. Our data have allowed us to classify and understand immune responses in novel ways, suggesting many further avenues of enquiry and indicating previously unrecognized relationships between cell division and eventual cell fate.

The avidity spectrum of T cell receptor interactions accounts for T cell anergy in a double transgenic model.

The mechanism of self-tolerance in the CD4(+) T cell compartment was examined in a double transgenic (Tg) model in which T cell receptor (TCR)-alpha/beta Tg mice with specificity for the COOH-terminal peptide of moth cytochrome c in association with I-Ek were crossed with antigen Tg mice. Partial deletion of cytochrome-reactive T cells in the thymus allowed some self-specific CD4(+) T cells to be selected into the peripheral T cell pool. Upon restimulation with peptide in vitro, these cells upregulated interleukin (IL)-2 receptor but showed substantially lower cytokine production and proliferation than cells from TCR Tg controls. Proliferation and cytokine production were restored to control levels by addition of saturating concentrations of IL-2, consistent with the original in vitro definition of T cell anergy. However, the response of double Tg cells to superantigen stimulation in the absence of exogenous IL-2 was indistinguishable from that of TCR Tg controls, indicating that these self-reactive cells were not intrinsically hyporesponsive. Measurement of surface expression of Tg-encoded TCR alpha and beta chains revealed that cells from double Tg mice expressed the same amount of TCR-beta as cells from TCR Tg controls, but only 50% of TCR-alpha, implying expression of more than one alpha chain. Naive CD4(+) T cells expressing both Tg-encoded and endogenous alpha chains also manifested an anergic phenotype upon primary stimulation with cytochrome c in vitro, suggesting that low avidity for antigen can produce an anergic phenotype in naive cells. The carboxyfluorescein diacetate succinimidyl ester cell division profiles in response to titered peptide +/- IL-2 indicated that expression of IL-2 receptor correlated with peptide concentration but not TCR level, whereas IL-2 production was profoundly affected by the twofold decrease in specific TCR expression. Addition of exogenous IL-2 recruited double Tg cells into division, resulting in a pattern of cell division indistinguishable from that of controls. Thus, in this experimental model, cells expressing more than one alpha chain escaped negative selection to a soluble self-protein in the thymus and had an anergic phenotype indistinguishable from that of low avidity naive cells. The data are consistent with the notion that avidity-mediated selection for self-reactivity in the thymus may lead to the appearance of anergy within the peripheral, self-reactive T cell repertoire, without invoking the induction of hyporesponsiveness to TCR-mediated signals.

Disease-modifying antirheumatic drugs, including methotrexate, sulfasalazine, gold, antimalarials, and penicillamine.

Recently, there has been an interest in rethinking the classification of antirheumatic drugs. Emphasis continues to be on aggressive control of inflammation in the early phase of rheumatoid arthritis. The mistake of extrapolating short-term clinical trial results to long-term outcomes has been appreciated, pointing to the need for long-term studies. Interest in the role of cytokines and their receptors in the inflammatory process continues, as well as in the cellular mechanisms of action of the various disease-modifying antirheumatic drugs (DMARDs). Troublesome toxicity profiles continue to be reported, and a consideration of efficacy-toxicity trade-offs are important. Methotrexate still shows long-term efficacy, and low-dose folinic acid has been shown to reduce toxicity but not efficacy. New information on other DMARDs is presented, ie, sulfasalazine inhibition of signal transduction, the effects of hydroxychloroquine on cytokines and lipid metabolism, and the immunosuppressive effects of bucillamine, a penicillamine-related compound.

Nonsteroidal anti-inflammatory drugs. Differential use in older patients.

The nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used medications, particularly in elderly patients, for both rheumatic and nonrheumatic conditions. Elderly patients are more prone to the adverse effects of these agents. Adverse effects are seen in almost every organ system, but the gastrointestinal tract is most frequently affected. Elderly patients are more at risk of adverse effects from a wide range of pharmacokinetic and pharmacodynamic interactions compared with younger patients. By cautious prescribing, including giving due consideration to these factors, the risks associated with NSAIDs in elderly patients can be minimised.

beta-Glucuronidase activity in liver and spleen homogenates of mice experimentally infected with Schistosoma mansoni.

A study on the beta-glucuronidase activity in liver and spleen homogenates of mice infected with an Egyptian strain of Schistosoma mansoni and of non infected control animals was carried out for a follow up period of four months. A decreased enzyme activity was observed in the spleen up to the 40th day after infection. From the 60th day on, the enzyme level in both liver and spleen was found above that in the control. The possible causes for such changes in enzyme activity are discussed.

Biochemical studies on beta-glucuronidase in the urinary bladder of normal and Schistosoma mansoni infected mice treated with hycanthone.

beta-Glucuronidase activity is elevated in the urine of patients with bilharziasis hematobium. In the present study the enzyme level was estimated in whole urinary bladder tissue homogenates of mice experimentally infected with Schistosoma mansoni. In the infected mice the enzyme activity is significantly higher than in the controls. The effect of the schistosomicidal drug hycanthone was also evaluated. Treatment with the drug did not affect the level of the enzyme activity in the infected mice; it induced an increase in the enzyme activity of the controls.

Functional capacity of the tryptophan-niacin pathway in the premenarchial phase and in the menopausal age.

Studies on the interrelationship between female hormones associated with reproduction and the vitamin B6-dependent enzymes along the kynurenin pathway of trytophan metabolism were carried out in girls with an age less, and more than 10 years (just before the onset of the first menstrual cycle), and in postmenapausal women with and without relative (excess) production of estradioll from the adrenal cortex. It is found that most of the determined metabolites are retained by the girls with age less than 10 years after tryptophan loading without and with vitamin B6 supplementation. Estradiol from either the ovaries (in girls just before menarch), or the adrenal cortex-in postmenopausal women with relative (excess) production of this hormone-interferes with the further degradation of 3-hydroxyanthranilic acid. However, this interference could be completely restored by vitamin B6 supplementation. The extra presence of a partial impairment in the kynureninase enzyme is also suggested in these postmenopausal women. In the latter case, this enzymatic activity could be partially resored by vitamin B6 supplementation. On the contrary, the enzymes: kynureninases and adrenocortical estradio. Pyridoxine supplementation partially corrected the inhibition especially that of 3-hydroxykynurenine transaminase enzyme.

The influence of sex, age, synthetic oestrogens, progestogens and oral contraceptives on the excretion of urinary tryptophan metabolites.

PIP: The excretion of urinary tryptophan metabolites was studied in normal and postmenopausal women and in women taking norethindrone and ethinyl estradiol, singly and in combination. The results showed that the altered tryptophan metabolism found in the preovulatory phase of the cycle and in postmenopausal women was the result of an interaction between Vitamin-B6 and endogenous sex hormones. During the preovulatory phase, endogenous estradiol disrupted the normal activity of the Vitamin-B6-dependent quinolinic acid decarboxylase, which resulted in the accumulation of bladder carcinogens in urine. During the postovulatory phase, endogenous progesterone and the production of metabolites antagonized this effect. Administration of naturally occurring progesterone and of ethinyl estradiol, alone and in combination with norethindrone, was able to counter the interaction between Vitamin-B6 and endogenous estradiol. It is suggested that the cyclic excretion pattern of endogenous bladder carcinogens in young, nonpregnant women may contribute, in part, to the low incidence of bladder cancer in women.^ieng