IntroductionHistones can mediate the binding of DNA and anti-DNA to the glomerular basement membrane (GBM). In ELISA histone/DNA/anti-DNA complexes are able to bind to heparan sulfate (HS), an intrinsic constituent of the GBM. We questioned whether histone containing immune complexes are able to bind to the GBM, and if so, whether the ligand in the GBM is HS. Monoclonal antibodies (mAbs) complexed to nucleosomal antigens and noncomplexed mAbs were isolated from culture supernatants of four IgG anti-nuclear mAbs. All noncomplexed mAbs showed strong anti-nucleosome reactivity in ELISA. One of them showed in addition anti-DNA reactivity in noncomplexed form. The other three mAbs only showed anti-DNA reactivity when they were complexed to nucleosomal antigens. After renal perfusion a fine granular binding of complexed mAbs to the glomerular capillary wall and activation of complement was observed in immunofluorescence, whereas noncomplexed mAbs did not bind. Immuno-electron microscopy showed binding of complexes to the whole width of the GBM. When HS in the GBM was removed by renal heparinase perfusion the binding of complexed mAb decreased, but did not disappear completely.We conclude that anti-nucleosome mAbs, which do not bind DNA, become DNA reactive once complexed to nucleosomal antigens. These complexed mAbs can bind to the GBM. The binding ligand in the GBM is partly, but not solely, HS. Binding to the GBM of immune complexes containing nucleosomal material might be an important event in the pathogenesis of lupus nephritis. (J. Clin. Invest. 1994. 94:568-577.)

Using polyclonal and monoclonal antihistone antisera, histones were identified in all patients with DPGN and their presence was associated with a decrease of HS staining. Nucleosomes were identified in five of 11 patients with DPGN and in two of six patients with MGN. This is the first demonstration of nucleosomes in glomerular deposits in SLE nephritis.

Objective: To study the efficacy and safety of low-dose oral tetrahydrocannabinol (THC) in the treatment of dementia-related neuropsychiatric symptoms (NPS).Methods: This is a randomized, double-blind, placebo-controlled study. Patients with dementia and clinically relevant NPS were randomly assigned to receive THC 1.5 mg or matched placebo (1:1) 3 times daily for 3 weeks. Primary outcome was change in Neuropsychiatric Inventory (NPI), assessed at baseline and after 14 and 21 days. Analyses were based on intention-to-treat.Results: Twenty-four patients received THC and 26 received placebo. NPS were reduced during both treatment conditions. The difference in reduction from baseline between THC and placebo was not significant (mean difference NPI total : 3.2, 95% confidence interval [CI] 23.6 to 10.0), nor were changes in scores for agitation (Cohen-Mansfield Agitation Inventory 4.6, 95% CI 23.0 to 12.2), quality of life (Quality of Life-Alzheimer's Disease 20.5, 95% CI 22.6 to 1.6), or activities of daily living (Barthel Index 0.6, 95% CI 20.8 to 1.9). The number of patients experiencing mild or moderate adverse events was similar (THC, n 5 16; placebo, n 5 14, p 5 0.36). No effects on vital signs, weight, or episodic memory were observed.Conclusions: Oral THC of 4.5 mg daily showed no benefit in NPS, but was well-tolerated, which adds valuable knowledge to the scarce evidence on THC in dementia. The benign adverse event profile of this dosage allows study of whether higher doses are efficacious and equally welltolerated. Classification of evidence:This study provides Class I evidence that for patients with dementiarelated NPS, low-dose THC does not significantly reduce NPS at 21 days, though it is welltolerated. Neurology ® 2015;84:2338-2346 GLOSSARY AD 5 Alzheimer disease; AE 5 adverse event; CCGIC 5 Caregiver Clinical Global Impression of Change; CI 5 confidence interval; CMAI 5 Cohen-Mansfield Agitation Inventory; NPI 5 Neuropsychiatric Inventory; NPS 5 neuropsychiatric symptoms; PAL WMS-R 5 Paired Associate Learning Wechsler Memory Scale-Revised; QoL-AD 5 Quality of Life-Alzheimer's Disease Scale; RCT 5 randomized controlled trial; THC 5 D-9-tetrahydrocannabinol.