Analysis of maternal–offspring HLA compatibility,parent‐of‐origin effects,and noninherited maternal antigen effects for HLA–DRB1 in systemic lupus erythematosus

Objective

Genetic susceptibility to systemic lupus erythematosus (SLE) is well established, with the HLA class II DRB1 and DQB1 loci demonstrating the strongest association. However, HLA may also influence SLE through novel biologic mechanisms in addition to genetic transmission of risk alleles. Evidence for increased maternal–offspring HLA class II compatibility in SLE and differences in maternal versus paternal transmission rates (parent‐of‐origin effects) and nontransmission rates (noninherited maternal antigen [NIMA] effects) in other autoimmune diseases have been reported. Thus, we investigated maternal–offspring HLA compatibility, parent‐of‐origin effects, and NIMA effects at DRB1 in SLE.

Methods

The cohort comprised 707 SLE families and 188 independent healthy maternal–offspring pairs (total of 2,497 individuals). Family‐based association tests were conducted to compare transmitted versus nontransmitted alleles (transmission disequilibrium test) and both maternally versus paternally transmitted (parent‐of‐origin) and nontransmitted alleles (using the chi‐square test of heterogeneity). Analyses were stratified according to the sex of the offspring. Maternally affected offspring DRB1 compatibility in SLE families was compared with paternally affected offspring compatibility and with independent control maternal–offspring pairs (using Fisher's test) and was restricted to male and nulligravid female offspring with SLE.

Results

As expected, DRB1 was associated with SLE (P < 1 × 10⁻⁴). However, mothers of children with SLE had similar transmission and nontransmission frequencies for DRB1 alleles when compared with fathers, including those for the known SLE risk alleles HLA–DRB1*0301, *1501, and *0801. No association between maternal–offspring compatibility and SLE was observed.

Conclusion

Maternal–offspring HLA compatibility, parent‐of‐origin effects, and NIMA effects at DRB1 are unlikely to play a role in SLE.

     

The pharmacological advantage of prolonged dose rate gemcitabine is restricted to patients with variant alleles of cytidine deaminase c.79A>C

Aim: Controversy exists over the optimal dosing for the nucleoside analogue gemcitabine. A pharmacological advantage is achieved by prolonging infusion times but evidence for a clinical benefit has been conflicting. We hypothesized that polymorphisms in genes involved in gemcitabine accumulation, particularly the cytidine deaminase CDA c.79A>C, may influence the optimal dosing regimen in individual patients. Methods: DNA was collected from 32 patients participating in a randomized crossover study comparing 30‐min with 100‐min infusions of gemcitabine. The relationships between seven polymorphisms among three genes (CDA, RRM1 and DCK) and (i) gemcitabine triphosphate accumulation; (ii) gemcitabine‐induced toxicity; and (iii) dose delivery were examined for each infusion time and week of administration. Results: There were trends for increased accumulation of gemcitabine‐triphosphate (GEM‐TP) with the variant alleles of CDA c.79A>C, and RRM1‐37C>A and ‐524T>C but none of these reached statistical significance in a univariate analysis. In a multivariable model there were significant effects of infusion duration and week of administration on GEM‐TP accumulation. There were significant interactions between CDA c.79A>C (P = 0.01) and RRM1‐37C>A (P = 0.019) genotypes, infusion time, and arm. More patients with one or two CDA c.79 variant alleles had doses delays (57 vs 13 %, P = 0.03) and a pharmacological advantage for prolonged infusion after week 1. Conclusion: It is important to consider both pharmacokinetics and pharmacogenetics in optimizing gemcitabine accumulation. This represents a classical interaction between genes and environment and provides support for the consideration of both CDA genotype and infusion duration in development of an individualized dosing strategy.     

Analysis of Flavonoid‐Based Pharmacophores that Inhibit Aggrecanases (ADAMTS‐4 and ADAMTS‐5) and Matrix Metalloproteinases Through the Use of Topologically Constrained Peptide Substrates

Polyphenolic natural products from green tea and red wine have been identified as metalloproteinase inhibitors. Members from the flavonoid and stilbene families found to possess metalloproteinase inhibitory activities include (?)‐epigallocatechin gallate, (?)‐epicatechin gallate and piceatannol, but their minimally active pharmacophores have not been evaluated. The present study has examined compounds that are structural components of or structurally related to (?)‐epigallocatechin gallate, (?)‐epicatechin gallate and piceatannol for inhibition of aggrecanases and four representative matrix metalloproteinases. Piceatannol and pyrogallol were found to inhibit all aggrecanases and matrix metalloproteinases studied, indicating a crucial reliance on multiple hydroxyl groups for (?)‐epigallocatechin gallate, (?)‐epicatechin gallate and piceatannol activity. Differences in K_i values for pyrogallol as determined with two structurally distinct substrates indicated the likelihood that this compound binds in a non‐competitive modality. Further analysis showed that pyrogallol acts as an exosite inhibitor, consistent with the action of (?)‐epigallocatechin gallate. In contrast, piceatannol was shown to be a competitive binding inhibitor and showed no differences in apparent K_i values as determined by distinct substrates, illustrating the benefits of using two structurally distinct substrates to assist the analysis of protease inhibitors. The compounds identified here could be utilized to develop novel metalloproteinase probes or as fragment components of more active inhibitors.     

Differential projections from the vestibular nuclei to the flocculus and uvula-nodulus in pigeons (Columba livia)

The pigeon vestibulocerebellum is divided into two regions based on the responses of Purkinje cells to optic flow stimuli: the uvula-nodulus responds best to self-translation, and the flocculus responds best to self-rotation. We used retrograde tracing to determine whether the flocculus and uvula-nodulus receive differential mossy fiber input from the vestibular and cerebellar nuclei. From retrograde injections into the both the flocculus and uvula-nodulus, numerous cells were found in the superior vestibular nucleus (VeS), the cerebellovestibular process (pcv), the descending vestibular nucleus (VeD), and the medial vestibular nucleus (VeM). Less labeling was found in the prepositus hypoglossi, the cerebellar nuclei, the dorsolateral vestibular nucleus, and the lateral vestibular nucleus, pars ventralis. In the VeS, the differential input to the flocculus and uvula-nodulus was distinct: cells were localized to the medial and lateral regions, respectively. The same pattern was observed in the VeD, although there was considerable overlap. In the VeM, the majority of cells labeled from the flocculus were in rostral margins on the ipsilateral side, whereas labeling from uvula-nodulus injections was distributed bilaterally throughout the VeM. Finally, from injections in the flocculus but not the uvula-nodulus, moderate labeling was observed in a paramedian area, adjacent to the medial longitudinal fasciculus. In summary, there were clear differences with respect to the projections from the vestibular nuclei to functionally distinct parts of the vestibulocerebellum. Generally speaking, the mossy fibers to the flocculus and uvula-nodulus arise from regions of the vestibular nuclei that receive input from the semicircular canals and otolith organs, respectively.     

Retrospective analysis of pimecrolimus cream 1% for treatment of facial vitiligo

OBJECTIVE: To explore the effectiveness of pimecrolimus cream 1% used twice daily (BID) for the treatment of facial vitiligo. METHODS: Patients who had used pimecrolimus cream 1% monotherapy BID for at least 3 months and who had photographs taken at baseline and after initiation of therapy were analyzed in a retrospective study. The total affected surface area (cm2) of facial vitiligo in the baseline and follow-up photographs was compared. The extent of facial depigmentation was scored using a 7-point scale (0 = no disease to 6 = 100% involvement). RESULTS: Eight patients met study entry criteria. Mean time from initiation of treatment to the final follow-up visit was 11 months (SD +/- 7.5 months). Mean affected surface area at baseline and follow-up were 79.40 cm2 and 17.96 cm2, respectively, (P = .012) with a mean percent improvement 72.5% (SD +/- 20.4%). Mean depigmentation score decreased from 2.8 at baseline to 1.4 at follow-up. No adverse events were reported. CONCLUSION: Pimecrolimus cream 1% may be a viable alternative to current therapies for the treatment of facial vitiligo.