Other Modifying Factors

g-chain (HbF) output. This occurs in 8p°-thalassemia, which is caused by deletions of variable size in the p-globin gene cluster, and in deletions removing only the 5' region of the p-globin gene promoter, which also result in high levels of HbA2. High g-chain output may also depend on cotransmission of hereditary persistence of fetal hemoglobin (HPFH), resulting from single-point mutations of the Ag or Gg promoter. The most common is a single-base C to T substitution at position — 158 upstream from the Gg gene, which is silent in normal subjects and p-thalassemia heterozygotes, but leads to increased HbF production in patients with erythropoietic stress, as occurs in homozygous p-thalassemia. The —158 Gg mutation is in linkage disequilibrium with the IVSII-I (G! A), frameshift 8 (-AA), and frameshift 6 (-A) mutations. This explains the mild phenotype that may result from the inheritance of these mutations. Another point mutation of the Ag promoter (— 196 C ! T) is in linkage with the p° 39 nonsense mutation in Sardinians. Homozygosity for this chromosome is associated with a clinically silent phenotype. Finally, also coinheritance of heterocellular hereditary persistence of fetal hemoglobin (HPFH), which may be linked or unlinked to the p-globin gene cluster, may lead to a mild phenotype. To date, three loci have been mapped: one at Xq22.2-q22.3, one on 6q22.3-q23.1, and one on 8q (which interacts with the Gg — 158 C ! T mutation), but many others are very likely to exist. In some cases, heterozygous p-thalassemia may lead to the phenotype of thalassemia intermedia instead of the asymptomatic carrier state. Known molecular mechanisms include the following:

The clinical phenotype of homozygous p-thalassemia may also be modified by the coinheritance of other genetic factors mapping outside the p-globin gene cluster. The best known of these modifying genes is the Gilbert mutation [i.e., the presence of the (TA)7 configuration instead of the (TA)6 in the TATA box of the gene encoding uridin-diphosphoglucuronyltransferase], which, when combined with thalassemia major or thalassemia intermedia or the p-thalassemia carrier state, leads to increased jaundice and increased risk of gallstones. Less defined modifying factors are genes coding for hereditary hemochromatosis and genes involved in bone metabo-lism.[10]

Getting Started With Dumbbells

Getting Started With Dumbbells

The use of dumbbells gives you a much more comprehensive strengthening effect because the workout engages your stabilizer muscles, in addition to the muscle you may be pin-pointing. Without all of the belts and artificial stabilizers of a machine, you also engage your core muscles, which are your body's natural stabilizers.

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