Bovine Spongiform Encephalopathy (BSE) and Milk

Bovina spongiformna encefalopatija (BSE) je prionska bolest goveda, koja se pojavila 1985. godine u Velikoj Britaniji i izazvala veliku epidemiju izrokovanu hranom. Oboljelo je više od milijun životinja. Bolest se širila izvozom britanskih prehrambenih proizvoda za goveda (mesno i koštano brašno), najviše u europske zemlje, zatim Kanadu, Sjedinjene Američke Države i Japan. BSE je prenosiva na ljude konzumacijom inficiranog mesa; više od 160 slućajeva ove »varijante« Creutzfeldt-Jacobove bolesti je bila potvrđena u Velikoj Britaniji, 26 u Francuskoj i rijetki slučajevi u drugim zemljama. Konatalna infekcija u potomaka inficiranih goveda se javlja u nekih 10 %. Mlijeko je od ogromne važnosti u ljudskoj prehrani, osobito djece, a infektivnost mlijeka u ovom času još nije sasvim jasna, i premda je malo vjerojatna, ipak najnovija istraživanja pokazuju, da je moguća u određenim uvjetima, i stoga su potrebna dalja istraživanja, te epidemiološke mjere za izolaciju mogućih rizičnih životinja. Za jednu drugu sličnu prionsku bolest, a to je scrapie, infektivnost mlijeka je dokazana. Situacija na svjetskom tržištu mlijeka je danas kaotična i zahtijevala bi usku suradnju odgovornih političara i ekonomista, uz stručni nadzor veterinara i liječnika u svijetu i u Hrvatskoj.BSE, a prion disease of cattle, started about in 1985 and caused a large food epidemic in Great Britain with over a million of infected animals. The disease has spread, by British foodstuff export, involving most of the European countries, Canada, United States of America and Japan. BSE was transmissible for humans by infected meat consumation; over 160 cases of this »variant« Creutzfeldt-Jacob disease were confirmed in Great Britain, 26 in France and rare cases in many other countries. Connatal infection in cattle ocurrs in some 10 percent. Milk appears of enormous importance for humans in general, but particularly for children. Its BSE infectivity has not been clear at present as shown by recent studies in another similar prion disease, scrapie. The situation in the world milk market appears actually chaotic requiring a close cooperation between authorithies in politic and economy as well as between veterinary and human medical officers studying the situation in Croatia

Angiotensin-converting enzyme insertion/deletion gene polymorphism and interferon-β treatment response in multiple sclerosis patients: a preliminary report.

We investigated the effect of the functional insertion/ deletion (I/D) polymorphism in the angiotensin- converting enzyme (ACE) gene on the response to interferon-β (IFN-β) therapy in Croatian and Slovenian patients with multiple sclerosis (MS). A total of 275 IFN-β treated MS patients [162 responders (Rs) and 113 nonresponders (NRs)] were genotyped by PCR. The ACE I/D genotype distribution and allele frequencies did not differ between female Rs and NRs. However, male NRs tended to have a greater prevalence of the DD genotype (P=0.073 ; odds ratio: 2.64 ; 95% confidence interval: 0.91–7.60) and a significantly higher frequency of the D allele (P=0.022 ; odds ratio: 2.43 ; 95% confidence interval: 1.13–5.20) than male Rs. Multiple forward stepwise regression analysis indicated that the negative response to IFN-β therapy was associated with the ACE-DD genotype in men ( β=0.371 ; multiple R2 change: 0.132 ; P=0.009) and a higher pretreatment relapse rate in both men ( β=−0.438 ; multiple R2 change: 0.135 ; P=0.015) and women ( β=−0.208 ; multiple R2 change: 0.042 ; P=0.034). The ACE I/D polymorphism and pretreatment relapse rate accounted for ∼26.7% of the IFN-β response variability among the men in the sample. Further studies of a larger number of MS patients from different populations are necessary to evaluate these preliminary findings

The role of TPA I/D and PAI-1 4G/5G polymorphisms in multiple sclerosis.

Previous studies have shown impaired fibrinolysis in multiple sclerosis (MS) and implicated extracellular proteolytic enzymes as important factors in demyelinating neuroinflammatory disorders. Tissue-type plasminogen activator (t-PA) and its inhibitor (PAI-1) are key molecules in both fibrinolysis and extracellular proteolysis. In the present study, an association of the TPA Alu I/D and PAI-1 4G/5G polymorphisms with MS was analyzed within the Genomic Network for Multiple Sclerosis (GENoMS). METHODS: The GENoMS includes four populations (Croatian, Slovenian, Serbian, and Bosnian and Herzegovinian) sharing the same geographic location and a similar ethnic background. A total of 885 patients and 656 ethnically matched healthy blood donors with no history of MS in their families were genotyped using PCR-RFLP. RESULTS: TPA DD homozygosity was protective (OR = 0.79, 95% CI 0.63-0.99, P = 0.037) and PAI 5G5G was a risk factor for MS (OR = 1.30, 95% CI 1.01-1.66, P = 0.038). A significant effect of the genotype/carrier combination was detected in 5G5G/I carriers (OR = 1.39 95% CI 1.06-1.82, P = 0.017). CONCLUSIONS: We found a significantly harmful effect of the combination of the PAI-1 5G/5G genotype and TPA I allele on MS susceptibility, which indicates the importance of gene-gene interactions in complex diseases such as MS

Association of circadian rhythm genes ARNTL/BMAL1 and CLOCK with multiple sclerosis

Prevalence of multiple sclerosis varies with geographic latitude. We hypothesized that this fact might be partially associated with the influence of latitude on circadian rhythm and consequently that genetic variability of key circadian rhythm regulators, ARNTL and CLOCK genes, might contribute to the risk for multiple sclerosis. Our aim was to analyse selected polymorphisms of ARNTL and CLOCK, and their association with multiple sclerosis. A total of 900 Caucasian patients and 1024 healthy controls were compared for genetic signature at 8 SNPs, 4 for each of both genes. We found a statistically significant difference in genotype (ARNTL rs3789327, P = 7.5.10(-5); CLOCK rs6811520 P = 0.02) distributions in patients and controls. The ARNTL rs3789327 CC genotype was associated with higher risk for multiple sclerosis at an OR of 1.67 (95% CI 1.35-2.07, P = 0.0001) and the CLOCK rs6811520 genotype CC at an OR of 1.40 (95% CI 1.13-1.73, P = 0.002). The results of this study suggest that genetic variability in the ARNTL and CLOCK genes might be associated with risk for multiple sclerosis

The Role of TPA I/D and PAI-1 4G/5G Polymorphisms in Multiple Sclerosis

Background. Previous studies have shown impaired fibrinolysis in multiple sclerosis (MS) and implicated extracellular proteolytic enzymes as important factors in demyelinating neuroinflammatory disorders. Tissue-type plasminogen activator (t-PA) and its inhibitor (PAI-1) are key molecules in both fibrinolysis and extracellular proteolysis. In the present study, an association of the TPA Alu I/D and PAI-1 4G/5G polymorphisms with MS was analyzed within the Genomic Network for Multiple Sclerosis (GENoMS). Methods. The GENoMS includes four populations (Croatian, Slovenian, Serbian, and Bosnian and Herzegovinian) sharing the same geographic location and a similar ethnic background. A total of 885 patients and 656 ethnically matched healthy blood donors with no history of MS in their families were genotyped using PCR-RFLP. Results. TPA DD homozygosity was protective (OR = 0.79, 95% CI 0.63–0.99, P=0.037) and PAI 5G5G was a risk factor for MS (OR = 1.30, 95% CI 1.01–1.66, P=0.038). A significant effect of the genotype/carrier combination was detected in 5G5G/I carriers (OR = 1.39 95% CI 1.06–1.82, P=0.017). Conclusions. We found a significantly harmful effect of the combination of the PAI-1 5G/5G genotype and TPA I allele on MS susceptibility, which indicates the importance of gene-gene interactions in complex diseases such as MS

Identification of rare genetic variation of NLRP1 gene in familial multiple sclerosis

The genetic etiology and the contribution of rare genetic variation in multiple sclerosis (MS) has not yet been elucidated. Although familial forms of MS have been described, no convincing rare and penetrant variants have been reported to date. We aimed to characterize the contribution of rare genetic variation in familial and sporadic MS and have identified a family with two sibs affected by concomitant MS and malignant melanoma (MM). We performed whole exome sequencing in this primary family and 38 multiplex MS families and 44 sporadic MS cases and performed transcriptional and immunologic assessment of the identified variants. We identified a potentially causative homozygous missense variant in NLRP1 gene (Gly587Ser) in the primary family. Further possibly pathogenic NLRP1 variants were identified in the expanded cohort of patients. Stimulation of peripheral blood mononuclear cells from MS patients with putatively pathogenic NLRP1 variants showed an increase in IL-1B gene expression and active cytokine IL-1β production, as well as global activation of NLRP1-driven immunologic pathways. We report a novel familial association of MS and MM, and propose a possible underlying genetic basis in NLRP1 gene. Furthermore, we provide initial evidence of the broader implications of NLRP1-related pathway dysfunction in MS

Genotype distribution of the <i>CLOCK</i> polymorphisms of the 268 IRSA patients and 284 controls.

<p>Genotype distribution of the <i>CLOCK</i> polymorphisms of the 268 IRSA patients and 284 controls.</p