CREUTZFELDT-JACOB DISEASE: A GOLGI STUDY

A cerebral biopsy of a patient with Creutzfeldt-Jacob (C-J) disease was examined with the Golgi method. Distortion of soma and neuronal processes associated with vacuolization of the neuropil was observed. The main findings were decreased numbers of basal dendrites and of branches of the apical dendrite of the pyramidal cells, marked loss of synaptic spines, and varicosities in the proximal segment of some apical and basal dendrites. These changes, though non-specific, may be interpreted as the result of deafferentation, although primary reactions related to C-J disease cannot be ruled out. These changes underline the intense disruption of intracortical connections which takes place in this condition in addition to the neuronal loss.     

The genetic interaction between VKORC1 c1173t and calumenin a29809g modulates the anticoagulant response of acenocoumarol

BACKGROUND: The efficacy of oral anticoagulant therapy is largely conditioned by both environmental and genetic factors. Objectives: To attempt to define the genetic profile involved in the response to this treatment. PATIENTS AND METHODS: We selected 100 men younger than 75 years, with non-valvular atrial fibrillation, who started anticoagulation with acenocoumarol following the same protocol: 3 mg for three consecutive days. Then, doses were individually adjusted to achieve a steady International Normalized Ratio (INR). The basal plasma level and the level after 3 days were obtained, and the INR was determined. We studied five functional polymorphisms: FVII -323 Del/Ins, CYP2C*9, VKORC1 c1173t, calumenin (CALU) R4Q and CALU a29809g. The dose required for a steady INR was also recorded. RESULTS: Only the VKORC1 genotype had significant impact on the efficacy of therapy. Carriers of the 1173t allele were significantly more sensitive to therapy for 3 days [INR 2.07 (1.59-2.87) vs. 1.74 (1.30-2.09); P = 0.015] and they needed lower acenocoumarol doses to stabilize their INR (15.8 +/- 5.6 vs. 19.5 +/- 6.0 mg week(-1); P = 0.004). Its effect was exacerbated by combination with the CALU a29809g polymorphism. Carriers of both variants (27% of the sample) achieved the highest INR [2.26 (1.70-3.32)] and required the lowest dose (14.1 +/- 5.1 mg week(-1)). This genetic profile was particularly relevant in patients with INR >or= 3.5 at the start of therapy (P = 0.005; odds ratio = 6.67, 95% confidence interval = 1.32-37.43). CONCLUSIONS: Our results suggest that CALU a29809g might be a new genetic factor involved in the pharmacogenetics of anticoagulant therapy, and confirm that specific genetic profiles defined by different polymorphisms will determine the initial response and dose required to achieve a stable and safe INR.