SUMMARYFour patients of 283 liver-transplant recipients (1´4%) developed de novo immune-mediated hepatitis approximately 2 years after transplantation. Antibodies showing an unusual liver/kidney cytoplasmic staining pattern were detected in the sera of all four patients and one of them was used to screen a human liver cDNA expression library with the aim of identifying the antigenic target of these newly developed antibodies. After cloning and sequencing the gene, it was identified as the gene encoding the glutathion-S-transferase T1 (GSTT1), a 29-kD molecular weight protein, expressed abundantly in liver and kidney. Sera from the other three patients also contained anti-GSTT1 antibodies, two of them demonstrated by immunoblot analysis against the recombinant antigen and the other, which was negative by immunoblot, gave a positive reaction when used directly to screen the same library, suggesting it to be directed to a conformational epitope. The GSTT1 enzyme is the product of a single polymorphic gene that is absent from 20% of the Caucasian population. When we analysed the GSTT1 genotype of the four patients described above, we found that this gene is absent from all of them. Three donor paraffin embedded DNA samples were available and were shown to be positive for GSSTT1 genotype. In accordance with these results, we suggest that this form of post-transplant de novo immune hepatitis, that has been reported as autoimmune hepatitis by others, could be the result of an antigraft reaction in individuals lacking the GSTT1 phenotype, in which the immune system recognizes the GSTT1 protein as a non-self antigen, being the graft dysfunction not the result of an autoimmune reaction, but the consequence of an alo-reactive immune response.

Introduction: Large variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways. Methods: Genome Research at Fundacio ACE (GR@ACE) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, GR@ACE series were meta-analyzed with additional genome-wide association study data sets. Results: We classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444. Discussion: The regulation of vasculature is a prominent causal component of probable AD. GR@ACE meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series.

BACKGROUND:Disentangling the genetic constellation underlying Alzheimer's disease (AD) is important. Doing so allows us to identify biological pathways underlying AD, point towards novel drug targets and use the variants for individualised risk predictions in disease modifying or prevention trials. In the present work we report on the largest genome-wide association study (GWAS) for AD risk to date and show the combined utility of proven AD loci for precision medicine using polygenic risk scores (PRS). METHODS:Three sets of summary statistics were included in our meta-GWAS of AD: an Spanish casecontrol study (GR@ACE/DEGESCO study, n = 12,386), the case-control study of International Genomics of Alzheimer project (IGAP, n = 82,771) and the UK Biobank (UKB) AD-by-proxy case-control study (n=314,278). Using these resources, we performed a fixed-effects inversevariance-weighted meta-analysis. Detected loci were confirmed in a replication study of 19,089 AD cases and 39,101 controls from 16 European-ancestry cohorts not previously used. We constructed a weighted PRS based on the 39 AD variants. PRS were generated by multiplying the genotype dosage of each risk allele for each variant by its respective weight, and then summing across all variants. We first validated it for AD in independent data (assessing effects of subthreshold signal, diagnostic certainty, age at onset and sex) and tested its effect on risk (odds for disease) and age at onset in the GR@ACE/DEGESCO study. FINDINGS:Using our meta-GWAS approach and follow-up analysis, we identified novel genome-wide significant associations of six genetic variants with AD risk (rs72835061-CHRNE, rs2154481-APP, rs876461-PRKD3/NDUFAF7, rs3935877-PLCG2 and two missense variants: rs34173062/rs34674752 in SHARPIN gene) and confirmed a stop codon mutation in the IL34 gene increasing the risk of AD (IL34-Tyr213Ter), and two other variants in PLCG2 and HS3ST1 regions. This brings the total number of genetic variants associated with AD to 39 (excluding APOE). The PRS based on these variants was associated with AD in an independent clinical ADcase control dataset (OR=1.30, per 1-SD increase in the PRS, 95%CI 1.18-1.44, p = 1.1×10 -7 ), a similar effect to that in the GR@ACE/DEGESCO (OR=1.27, 95%CI 1.23-1.32, p = 7.4×10 -39 ). We then explored the combined effects of these 39 variants in a PRS for AD risk and age-at-onset stratification in GR@ACE/DEGESCO. Excluding APOE, we observed a gradual risk increase over the 2% tiles; when comparing the extremes, those with the 2% highest risk had a 2.98-fold (95% CI 2.12-4.18, p = 3.2×10 -10 ) increased risk compared to those with the 2% lowest risk (p = 5.9×10 -10 ). Using the PRS we identified APOE ɛ33 carriers with a similar risk as APOE ɛ4 heterozygotes carriers, as well as APOE ɛ4 heterozygote carriers with a similar risk as APOE ɛ4 homozygote. Considering age at onset; there was a 9-year difference between median onset of AD the lowest risk group and the highest risk group (82 vs 73 years; p = 1.6×10 -6 ); a 4-year median onset diff...

Objective.-To describe the statuslike pattern of SUNCT (short-lasting unilateral neuralgiform pain with conjunctival injection and tearing) in two young women.Background.-SUNCT syndrome is a rare condition characterized by a short-lasting periocular pain associated with marked autonomic symptoms. Twenty-five cases have been reported in the literature with a high preponderance of males and a mean age of 51 years. The frequency of episodes shows a wide variability, not just among individuals but also in the same patient, and a statuslike pattern of almost continuous attacks has been described.Methods.-We report the cases of two young women (aged 26 and 23 years) with typical SUNCT features who suffered bouts of up to 60 paroxysms of pain per hour. Paraclinical investigations showed no abnormalities.Conclusions.-Although unusual, paroxysms in SUNCT may overlap into a clinical status. A strong relationship with hormonal changes was noted in one patient. In both cases, the pain was refractory to treatment with indomethacin, carbamazepine, and hypnotics, and only intravenous methylprednisolone with oral carbamazepine may have been partially effective in one case. Key words: SUNCT, unilateral headaches, steroids, carbamazepineAbbreviations: SUNCT short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing ( Headache 2001;41:826-829) In 1978, Sjaastad et al 1 described an entity termed SUNCT (short-lasting unilateral neuralgiform pain with conjunctival injection and tearing) characterized by recurrent, brief (15 to 120 seconds) unilateral pain attacks localized in the periocular area, with a rather abrupt onset and end, associated with marked ipsilateral autonomic features (massive conjunctival injection, watering of the eye, rhinorrhea, subclinical forehead sweating, and changes in cardiovascular variables). SUNCT has been classified among the trigeminal autonomic cephalgias and new diagnostic criteria have recently been proposed. 2,3 Generally, SUNCT starts around aged 51 years, with a range between 41 and 70 years for most cases. 4 Until 1994 when two women were reported, only men had been described. 5 The sex ratio for 25 reported cases is 2.57 men for every woman. 4 The frequency of attacks shows great variability not only between individuals but also in the same patient. The number of paroxysms may range from a few attacks per day to nearly continuous attacks, in what has been termed SUNCT status , which is an almost unbearable condition due to the intensity and frequency of the attacks. [6][7][8] We describe the statuslike pattern of the SUNCT syndrome in two young women. METHODSThe clinical notes of 254 patients with a diagnosis of cluster-type headache were reviewed. SUNCT was diagnosed when the patients had moderate to severe,

We evaluated the efficacy of intravenous boluses of methylprednisolone followed by prednisone as a prophylactic treatment for episodic cluster headache. Fourteen male patients (mean age, 42.54 years) with episodic cluster headache were treated with 250-mg boluses of methylprednisolone on 3 consecutive days, followed by prednisone (90 mg/day orally) with gradual tapering in four weeks. Headache parameters of the active phases treated with methylprednisolone were compared with those of previous active phases in the same patients treated with other prophylactic medications. The primary efficacy criterion was decrease in the frequency of attacks during the first month of treatment. The statistical differences were calculated using Wilcoxon's test. The attacks were significantly less frequent in the active phases treated with methylprednisolone boluses than those treated with other medications ( p<0.05). This treatment seems to be more effective than the usual prophylactic treatments for episodic cluster headache.