IntroductionGlomerulonephritis is a major cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). Deposition of autoantibodies in the glomeruli plays a key role in the development of lupus nephritis (LN). Different groups have proposed that either anti-nucleosome antibodies or antibodies that bind the intrinsic renal antigen, α-actinin, are central to the pathogenesis of LN. These theories have been based mainly on cross-sectional studies in patients and on experiments in animal models. No previous longitudinal studies have compared the relationships between levels of these antibodies and markers of renal function. We assessed how well anti-α-actinin, anti-nucleosome and anti-double-stranded DNA (anti-dsDNA) antibodies reflected renal outcome measures in patients with new-onset LN followed for up to 2 years.MethodsRenal disease activity was monitored by measuring urine protein/creatinine ratio (PCR), serum albumin and a composite outcome of renal remission. At each time point, anti-nucleosome and anti-α-actinin antibodies were measured by enzyme-linked immunosorbent assay. High-avidity anti-dsDNA antibodies were measured using the Farrzyme assay. We analysed relationships between levels of the three antibodies and between antibody levels and renal outcome measures over time.ResultsLevels of anti-nucleosome and anti-dsDNA were positively correlated with each other (r = 0.6, P = 0.0001) but neither correlated with anti-α-actinin level. At baseline, mean anti-nucleosome levels were higher in patients with LN than in healthy controls (0.32 versus 0.01, P < 0.001). The same was true for anti-dsDNA antibodies (0.50 versus 0.07, P < 0.001) but not for anti-α-actinin (0.33 versus 0.29). Over the follow-up period, anti-nucleosome and anti-dsDNA levels associated positively with urine PCR (P = 0.041 and 0.051, respectively) and negatively with serum albumin (P = 0.027 and 0.032, respectively). Both anti-nucleosome and anti-dsDNA levels were significantly lower during renal remission than when renal disease was active (P = 0.002 and 0.003, respectively). However, there was no relationship between anti-α-actinin levels and urine PCR, serum albumin or remission status.ConclusionsThis prospective longitudinal clinical study is the first to compare levels of anti-nucleosome, anti-dsDNA and anti-α-actinin antibodies in the same patients with SLE. Our results support the concept that, in the majority of patients, anti-nucleosome antibodies play a major role in pathogenesis of LN, in contrast to anti-α-actinin antibodies.

Some ellipticine derivative salts, including 9-chloro-2-methylellipticinium (CME), have been found to have a marked selectivity against all eight brain tumor cell lines of the U.S. National Cancer Institute's disease-oriented in vitro screen. We initiated in vivo antitumor studies to explore the feasibility for further development of this class of compounds. We found that CME was extremely toxic to nude mice when given i.p. at a dose of 25 mg/kg for 3 consecutive days. Animals treated by this route experienced an increase in hepatic transaminases and histopathological changes in the liver, compatible with mitochondrial damage. In contrast, when the portal circulation was bypassed and the same dose of CME was given i.v., animals tolerated daily bolus injections for 5 consecutive days. This 5-day i.v. bolus schedule had consistent antitumor activity, with 28.1% growth delay on s.c. implanted human U251 gliomas. When the potentially high peaks of CME in the portal circulation were avoided by using a 3-day continuous infusion with osmotic minipumps implanted i.p. to release 3.4 mg kg(-1) h(-1) or 6.6 mg kg(-1) h(-1) CME, there were only modest increases in liver enzymes and leukopenia, but no meaningful antitumor activity was observed. In contrast, continuous infusion in the s.c. space was well tolerated and was accompanied by a demonstrable growth delay in s.c. U251 human gliomas of 37.8%. When CME was used in conjunction with carmustine, etoposide or cisplatin, no synergistic activities were observed, but additive effects were demonstrated. Our pharmacokinetic and disposition studies with CME argue against the notion that large and invasive tumors in the brain lack blood-brain barrier features. When CME was used in animals bearing orthotopically implanted U251 gliomas in the brain of nude mice, the survival of the treated animals was not better than vehicle controls, and the addition of CME to carmustine therapy did not improve the survival of those animals treated with carmustine alone. We conclude that, in spite of its marked cytotoxicity in vitro on a variety of human brain tumor cell lines, including U251 glioma cells, CME has a modest antitumor effect on extracranially implanted U251 glioma tumors, and no beneficial effect in animals bearing the same U251 tumor in the brain, owing to a poor penetration into the brain parenchyma.

Abstract. We investigate the possibility of constructing Kochen-Specker uncolorable sets of idempotent matrices whose entries lie in various rings, including the rational numbers, the integers, and finite fields. Most notably, we show that there is no Kochen-Specker coloring of the n × n idempotent integer matrices for n ≥ 3, thereby illustrating that Kochen-Specker contextuality is an inherent feature of pure matrix algebra. We apply this to generalize recent no-go results on noncommutative spectrum functors, showing that any contravariant functor from rings to sets (respectively, topological spaces or locales) that restricts to the Zariski prime spectrum functor for commutative rings must assign the empty set (respectively, empty space or locale) to the matrix ring M n (R) for any integer n ≥ 3 and any ring R.An appendix by Alexandru Chirvasitu shows that Kochen-Specker colorings of idempotents in partial subalgebras of M 3 (F ) for a perfect field F can be extended to partial algebra morphisms into the algebraic closure of F .

Synthetic gene delivery systems employ multiple functions to enable safe and effective transport of DNA to target cells. Here, we describe metabolite-based poly(L-lysine) (PLL) modifiers that improve transfection by imparting both pH buffering and nanoparticle stabilization functions within a single molecular unit. PLL modifiers were based on morpholine (M), morpholine and niacin (MN), or thiomorpholine (TM). PLL modification with (MN) or (TM) imparted buffering function over the pH range of 5−7 both in solution and live cells and enhanced the stability of PLL DNA nanoparticles, which exhibited higher resistance to polyanion exchange and prolonged blood circulation. These properties translated into increased transfection efficiency in vitro coupled with reduced toxicity compared to unmodified PLL and PLL(M). Furthermore, PEG-PLL(MN) DNA nanoparticles transfected muscle tissue in vivo for >45 days following intramuscular injection. These polymer modifiers demonstrate the successful design of multifunctional units that improve transfection of synthetic gene delivery systems while maintaining biocompatibility.

SummaryThis rare cystic lesion has an approximate incidence of 1 in 200 000. This patient complained of abdominal distension and was diagnosed with a giant mesenteric cyst measuring 26 cm in height using CT imaging. She underwent a successful ultrasound-guided drainage, which is not previously reported in the literature. This represents utilisation of an established procedure in a novel situation. BACKGROUND