Overall negative trends for snow cover extent and duration in global mountain regions over 1982-2020.

Notwithstanding the large availability of data and models, a consistent picture of the snow cover extent and duration changes in global mountain areas is lacking for long-term trends. Here, model data and satellite images are combined by using Artificial Neural Networks to generate a consistent time series from 1982 to 2020 over global mountain areas. The analysis of the harmonized time series over 38 years indicates an overall negative trend of - 3.6% ± 2.7% for yearly snow cover extent and of - 15.1 days ± 11.6 days for snow cover duration. The most affected season by negative trends is winter with an average reduction in snow cover extent of - 11.5% ± 6.9%, and the most affected season by positive changes is spring with an average increase of 10% ± 5.9%, the latter mainly located in High Mountain Asia. The results indicated a shift in the snow regime located between the 80 s and 90 s of the previous century, where the period from 1982 to 1999 is characterized by a higher number of areas with significant changes and a higher rate of changes with respect to the period 2000-2020. This quantification can lead to a more accurate evaluation of the impact on water resources for mountainous communities.

Characterization of new mutations in the 5'-flanking region of the familial Mediterranean fever gene.

Familial Mediterranean fever (FMF) is a recessive autoinflammatory disease commonly found in the Mediterranean populations. Genetic diagnosis has developed since the discovery of the causative gene MEFV in 1997. As many patients could not be confirmed genetically by routine exon screening, we searched for mutations in the 5'-flanking region of this gene. Using denaturing gradient gel electrophoresis, we screened DNA from 108 patients with clinical FMF and 91 asymptomatic individuals. We found six novel sequence variants in a region extending -825 bp upstream of the first translated codon. To investigate the potential role of these variants in altering MEFV gene expression, we first characterized the MEFV promoter. Promoter mapping assays revealed that the region located between nucleotides -949 and -152 of the initiation codon was important for regulating expression of the gene. We identified a putative enhancer element between -571 and -414. Investigation of the sequence variants found in two patients demonstrated that c.-614C>G resulted in a 70% decrease in promoter activity, whereas c.-382C>T induced a 100% increase in activity, when compared to the wild type. We observed specific DNA-protein binding to both wild-type sites, suggesting that transcription factors may bind to these sequences to modulate MEFV expression.

Enhanced cytokine mRNA levels in attack-free patients with familial Mediterranean fever.

Familial Mediterranean fever (FMF) is a recessively inherited inflammatory disorder, characterized by recurrent attacks of fever and serositis. Screening of mutations in the causing gene (MEFV) now allows accurate diagnosis of FMF among other inflammatory conditions. It is well documented that secreted levels of some pro-inflammatory cytokines are elevated in FMF. Here, we investigated cytokine expression at the transcriptional level, in patients that could be genetically ascertained. We have measured the transcript abundance of tumor necrosis factor alpha, interleukin-1beta, interleukin-6 and interleukin-8, in circulating leukocytes and shown that these were more elevated in attack-free FMF patients than in controls (P=0.01, P=0.008, P=0.02, P=0.001 respectively). There was no significant difference according to MEFV genotype or colchicine treatment. Our results suggest that cytokine transcriptional pathways are misregulated in attack-free FMF patients, and further supports the hypothesis that these patients have subclinical inflammation between attacks.

The MICA region determines the first modifier locus in familial Mediterranean fever.

OBJECTIVE: Familial Mediterranean fever (FMF) is a genetically recessive inflammatory disease caused by mutations in the MEFV gene. Most patients of non-Ashkenazi Jewish ancestry or those who are homozygous for M694V manifest a severe disease course, but some express a mild form of the disease. We therefore searched for other genes which could possibly be implicated in the disease phenotype. We tested MICA (major histocompatibility complex class I chain-related gene A) because it has been associated with a number of other inflammatory disorders. METHODS: One hundred fifty FMF probands and their family members were evaluated. The MEFV gene was screened by a combination of denaturing gradient-gel electrophoresis, restriction fragment length polymorphism, and amplification refractory mutation system. The MICA transmembrane polymorphism in exon 5 was analyzed after biotin-labeled polymerase chain reaction products were loaded onto sequencing gels and subjected to autoradiography. RESULTS: The contribution of MICA to the FMF phenotype was confirmed after adjustment for the patient's ancestry and for the MEFV genotype. MEFV was individually the most important prognostic factor for the disease. However, the impact of M694V homozygosity on the age at disease onset (OR 2.3) was aggravated if patients also inherited MICA-A9 (OR 6.3). In contrast, the frequency of attacks was found to be dramatically reduced (OR 0.16) in patients with MICA-A4. CONCLUSION: We have identified the first FMF modifier locus, MICA. FMF is the first model of a Mendelian disease associated with MICA. These results clarify, at least partly, the inconsistent phenotype-MEFV correlation in FMF.

Familial Mediterranean fever in the 'Chuetas' of Mallorca: a question of Jewish origin or genetic heterogeneity.

Familial Mediterranean fever (FMF) is a hereditary disease commonly found among Jews, Armenians, Turks and Arabs. Recently, FMF was found in the 'Chuetas', a unique community on the island of Mallorca (Spain). To address the question of their possible Jewish origin, we analysed markers known to be linked to the gene responsible for FMF in Jews (MEFV) in this population. We found that 1/3 of the 16p13.3 chromosomes of the 'Chuetas' FMF patients bore the major ancestral haplotypes (S,S2) and their corresponding M694V and E148Q mutations, displayed by Jews from North Africa. Furthermore, we also detected a novel mutation (L110P) in this community. Yet 2/3 of these patients bore S negative haplotypes and lack the mutations commonly known to cause FMF. These results confirm that at least some of the 'Chuetas' share a common origin with Jews. However, they also provide evidence for the possibility of genetic heterogeneity in this disorder.

Inflammatory bowel disease in non-Ashkenazi Jews with familial Mediterranean fever.

Familial Mediterranean fever and inflammatory bowel disease are two inflammatory conditions. We showed that inflammatory bowel disease was particularly frequent and severe in non-Ashkenazi Jewish patients with familial Mediterranean fever.

Phenotype-genotype correlation in Jewish patients suffering from familial Mediterranean fever (FMF).

Familial Mediterranean Fever is one of the most frequent recessive disease in non-Ashkenazi Jews. The gene responsible for the disease (MEFV) has very recently been identified. The M694V ('MED') mutation was found in about 80% of the FMF Jewish (Iraqi and North African) chromosomes. To see if the presence of this mutation could be correlated with particular traits of the disease, we examined a number of clinical features in a panel of 109 Jewish FMF patients with 0, 1 or 2 MED mutations. We showed that homozygosity for this mutation was significantly associated with a more severe form of the disease. In homozygous patients, the disease started earlier (mean age 6.4 +/- 5 vs 13.6 +/- 8.9) and both arthritis and pleuritis were twice as frequent as in patients with one or no M694V mutation. Moreover, 3/3 patients with amyloidosis displayed two MED mutations. No association was found with fever, peritonitis, response to colchicine and erysipeloid eruption. The present result strongly suggests the potential prognostic value of the presence of this mutation.

Familial Mediterranean fever clinical and genetic features in Druzes and in Iraqi Jews: a preliminary study.

OBJECTIVE: A number of differences have been noted in clinical familial Mediterranean fever (FMF) among ethnic groups. Iraqi Jews and Druzes are characterized by less severe disease. The differences in disease expression raise the possibility of background genes peculiar to specific ethnic groups. METHODS: We analyzed a series of FMF linked microsatellite markers and searched for gene mutations in these 2 populations. RESULTS: We observed a conserved haplotype in 46% of the FMF druze chromosomes that was different from the Mediterranean haplotype but identical to the ARM3 haplotype. In contrast, 56% of the FMF chromosomes in Iraqi Jews displayed the same mutation as that found in Jews from North Africa. CONCLUSION: Variable expression in FMF is probably due to both allelic heterogeneity and/or modifier genes as well as environmental factors.