DNA methylation and developmental genes in lymphomagenesis--more questions than answers?

There is now considerable evidence suggesting that alterations in the DNA methylating machinery play an important role in tumorigenesis and tumour progression. For example, focal hypermethylation and generalised genomic demethylation are features of many different types of neoplasms. It is thought that tumorigenesis and tumour progression may be caused by hypermethylation induced mutational events and silencing of genes which control cellular proliferation and/or demethylation induced reactivation of genes which may only be required during embryological development. Consequently, we have begun to investigate the role of DNA methylation and developmental genes in malignant lymphoproliferative diseases. Previously, in all cases of non-Hodgkins lymphoma and leukemia studied, we have shown that the myogenic developmental gene Myf-3 is abnormally hypermethylated. In this review we discuss the possible significance of these findings since in vitro studies suggest that Myf-3 may play an important role in control of the cell cycle and therefore lymphomagenesis. In vitro and in vivo evidence suggests that PAX genes may also have oncogenic potential. The PAX family of developmental genes are involved in cellular differentiation, proliferation and cell migration. Expression of PAX3 in particular is associated with cellular mobility. Our previous studies have indicated that alternate regional expression of PAX genes may be controlled by DNA methylation. Therefore, we have proposed that abnormal methylation profiles of PAX3 may be associated with neoplastic transformation and/or metastatic potential. Results thus far reveal that the paired box of PAX3 is abnormally hypermethylated and the homeobox abnormally hypomethylated in lymphomas and leukemias. These new findings are consistent with our postulate and support the idea that inappropriate methylation induced activation or inactivation of developmental genes such as Myf-3 and PAX3 play an important role in lymphomagenesis and disease progression and that inspection of the methylation status of other developmental genes is warranted.     

Urodynamic picture in high spinal cord ischemia, induced by addictive use of cocaine. Report of a case

Since in vitro experiments had excluded interactions between Fe-gluconate (Fe-gluc) and magnesium-L-aspartate hydrochloride (MAH) in aqueous solutions the present in vivo studies seemed to be justified. Animal studies: Rats were kept on magnesium-(Mg)- and iron-(Fe)- sufficient and deficient diets. The intragastral administration of Fe-gluc significantly increased plasma Fe after 3 h, either given alone, or in combination with MAH (inducing hypermagnesemia). Same results were obtained when fortified diets were offered to Fe/Mg-deficient animals. Human studies: The combination of Fe-gluc (2 x 50 mg Fe per day, per os) plus MAH (2 x 7.5 mmol Mg per day, p.o.) was well tolerated by healthy volunteers. Single dose experiments revealed that Fe-gluc alone and in combination with MAH increased plasma Fe levels during 3 h to the same extent. Two groups of pregnant women with moderately reduced hemoglobin levels either received Fe-gluc (out-patients) or its combination with MAH (at least temporarily hospitalised because of preterm labor). Treatments were well tolerated. Hemoglobin levels did not further decrease, as expected without Fe supplements, during the course of pregnancy, thus indicating the therapeutic availability of the electrolytes in both study groups. Progesterone-induced constipation is frequently observed during pregnancy; hence stool softening reported by 50% of the women receiving Fe-gluc plus MAH (versus 33% in the Fe-gluc group) can be regarded as desirable effect. It is concluded that MAH does not interfere with the enteral absorption of Fe-gluc when both electrolytes are orally administered together. Taking both electrolytes together instead of 2 to 3 h apart from each other, as actually recommended, means a less complicated dosage regimen and probably improves compliance.