Objective. Different sets of diagnostic criteria have been proposed for Sjogren's syndrome (SS), but none have been validated with a large series of patients or in a multicenter study. We conducted the present study involving 26 centers from 12 countries (11 in Europe, plus Israel), with the goals of reaching a consensus on the diagnostic procedures for SS and defining classification criteria to be used in epidemiologic surveys and adopted by the scientific community.Methods. The study protocol was subdivided into two parts. For part I, questionnaires regarding both ocular and oral involvement were developed; they in-

Intracellular accumulations of mutant, misfolded proteins are major pathological hallmarks of amyotrophic lateral sclerosis (ALS) and related disorders. Recently, mutations in Sigma receptor 1 (SigR1) have been found to cause a form of ALS and frontotemporal lobar degeneration (FTLD). Our goal was to pinpoint alterations and modifications of SigR1 in ALS and to determine how these changes contribute to the pathogenesis of ALS. In the present study, we found that levels of the SigR1 protein were reduced in lumbar ALS patient spinal cord. SigR1 was abnormally accumulated in enlarged C-terminals and endoplasmic reticulum (ER) structures of alpha motor neurons. These accumulations co-localized with the 20s proteasome subunit. SigR1 accumulations were also observed in SOD1 transgenic mice, cultured ALS-8 patient's fibroblasts with the P56S-VAPB mutation and in neuronal cell culture models. Along with the accumulation of SigR1 and several other proteins involved in protein quality control, severe disturbances in the unfolded protein response and impairment of protein degradation pathways were detected in the above-mentioned cell culture systems. Furthermore, shRNA knockdown of SigR1 lead to deranged calcium signaling and caused abnormalities in ER and Golgi structures in cultured NSC-34 cells. Finally, pharmacological activation of SigR1 induced the clearance of mutant protein aggregates in these cells. Our results support the notion that SigR1 is abnormally modified and contributes to the pathogenesis of ALS.

ABSTRACT.Purpose: To examine the association between potential risk factors and the 14-year incidence of age-related maculopathy (ARM). Design: Population-based cohort study. Participants: At baseline, 946 volunteers participated in the study during 1986-88. These subjects were between 60 and 80 years of age and lived in the Østerbro district of Copenhagen. Excluding participants who had died since baseline, 359 subjects (97.3% of survivors) were re-examined 14 years later, during [2000][2001][2002]. A total of 31.8% (301/946) of the original material was included in the risk factor analyses. Methods: Participants underwent an ophthalmological examination at Rigshospitalet, the National University Hospital of Copenhagen. Similar standardized protocols for physical examination were used at the baseline and follow-up examinations. Age-related maculopathy lesions were determined by the same grader grading colour fundus photographs from both examinations using a modification of the Wisconsin Age-related Maculopathy Grading System protocol. Results: Of the 359 participants, 94 had incident early ARM and 52 had incident late ARM at follow-up in either eye. In logistic regression, the risk factors for early ARM or worse were as follows: cataract (odds ratio [OR] 2.8, 95% confidence interval [CI] 1.2-6.2); family history of ARM (OR 4.5, 95% CI 1.3-15.5), and alcohol consumption > 250 g/week (OR 4.6, 95% CI 1.1-19.2). High levels of apolipoprotein B (> 100 mg/l) decreased the risk of development of early ARM or worse (OR 0.4, 95% CI 0.2-0.8), while high levels of apolipoprotein A1 ( ‡ 150 mg/l) increased the risk of late ARM (OR 2.5, 95% CI 1.2-5.3). Advanced age at baseline was also associated with the incidence of late ARM (OR 2.0, 95% CI 1.4-2.9). Conclusions: These findings indicate a direct correlation between age, cataract, family history, alcohol consumption, the apolipoproteins A1 and B and the 14-year incidence of ARM.

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Intracellular accumulations of altered, misfolded proteins in neuronal and other cells are pathological hallmarks shared by many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Mutations in several genes give rise to familial forms of ALS. Mutations in Sigma receptor 1 have been found to cause a juvenile form of ALS and frontotemporal lobar degeneration (FTLD). We recently described altered localization, abnormal modification and loss of function of SigR1 in sporadic ALS. In order to further elucidate the molecular mechanisms underlying SigR1-mediated alterations in sporadic and familial ALS, we extended our previous studies using neuronal SigR1 knockdown cell lines. We found that loss of SigR1 leads to abnormal ER morphology, mitochondrial abnormalities and impaired autophagic degradation. Consistent with these results, we found that endosomal trafficking of EGFR is impaired upon SigR1 knockdown. Furthermore, in SigR1-deficient cells the transport of vesicular stomatitis virus glycoprotein is inhibited, leading to the accumulation of this cargo protein in the Golgi apparatus. Moreover, depletion of SigR1 destabilized lipid rafts and associated calcium mobilization, confirming the crucial role of SigR1 in lipid raft and intracellular calcium homeostasis. Taken together, our results support the notion that loss of SigR1 function contributes to ALS pathology by causing abnormal ER morphology, lipid raft destabilization and defective endolysosomal pathways.

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Bilateral diffuse uveal melanocytic proliferation (BDUMP) is a rare paraneoplastic intraocular disease that causes progressive visual loss in patients driven by an IgG factor associated with an underlying malignancy. Characteristic ocular findings include exudative retinal detachment, rapid cataract formation and uveal melanocytic tumours. The awareness and documentation of BDUMP has increased during the past decade, and the increasing amount of data collected demonstrates the effect of treatment with plasmapheresis and the value of diagnostic tools in BDUMP such as genetic and immunologic investigations. The literature of BDUMP has not been reviewed since 2003, and there is a growing need for an updated review on diagnosis and management of BDUMP. We review the literature and report a case of BDUMP with a white ciliary body tumour, iris rubeosis, increased iris pigmentation and cataract.