Frequency of TPMT alleles in Indian patients with acute lymphatic leukemia and effect on the dose of 6-mercaptopurine

Functional polymorphisms in the thiopurine methyl transferase (TPMT) gene have been associated with varying levels of enzyme activity and the occurrence of toxicity related to thiopurines. A total of 98 patients (66 pediatric and 32 adults) with precursor B acute lymphoblastic leukemia (Pre-B ALL) were evaluated for TPMT gene polymorphisms. The inability to tolerate 6-mercaptopurine (6-MP) at conventional doses was considered as a surrogate marker of hematologic toxicity. The allele frequency of TPMT*2, *3A, *3B and *3C in the study population was 0.5, 0, 0 and 2.6%, respectively, similar to the frequency observed in other Asian populations. Five patients were heterozygous for TPMT*3C variant allele, and one of these patient’s was compound heterozygous with TPMT*2 variant as the other allele. The impact of TPMT polymorphisms on the toxicity and treatment outcome was assessed in 66 pediatric patients only, as there was no variant TPMT detected in the adult patients. Three of the 5 patients (60%) heterozygous for TPMT*2 or TPMT*3C polymorphisms and 12/61 patients (20%) with wild type TPMT genotype had more than 10% of reduction of 6-MP dose (P = 0.07). The presence of TPMT polymorphisms did not seem to completely explain the variation in 6-MP toxicity in this small group of patients. Other novel variants in TPMT or variations in the genes involved in transport and biotransformation of 6-MP need to be evaluated in the Indian population.     

Perinatal Exposure to Bisphenol A or Diethylstilbestrol Increases the Susceptibility to Develop Mammary Gland Lesions After Estrogen Replacement Therapy in Middle-Aged Rats

The development of the mammary gland is a hormone-regulated event. Several factors can dysregulate its growth and make the gland more susceptible to cellular transformation. Among these factors, perinatal exposure to xenoestrogens and hormone replacement therapy has been associated with increased risk of developing breast cancer. Here, we assessed the effects induced by estrogen replacement therapy (ERT) in ovariectomized (OVX) middle-aged rats and whether perinatal exposure to diethylstilbestrol (DES) or bisphenol A (BPA) modified these effects in the mammary gland. Pregnant rats were orally exposed to vehicle, 5 μg DES/kg/day, or 0.5 or 50 μg BPA/kg/day from gestational day 9 until weaning. Then, 12-month-old offspring were OVX and treated with 17β-estradiol for 3 months. Morphological changes and the percentage of epithelial cells that proliferated or expressed estrogen receptor alpha (ESR1) and progesterone receptor (PR) were analyzed in mammary gland samples of 15-month-old animals. ERT induced lobuloalveolar hyperplasia and ductal cysts in the mammary gland of middle-aged rats, associated with a higher proliferation index of epithelial cells. Perinatal exposure to DES followed by ERT increased the number of cysts and induced the formation of fibroadenoma and ductal carcinoma in situ, without modifying the expression of ESR1 or PR. Also, after 3 months of ERT, BPA-exposed rats had a higher incidence of ductal hyperplasia and atypical lobular hyperplasia than animals under ERT alone. In conclusion, perinatal exposure to xenoestrogens increases the susceptibility of the mammary gland to develop cysts and hyperplastic lesions when confronted with ERT later in life.     

A direct in vivo measurement of the three‐dimensional orientation of the occlusal plane and of the sagittal discrepancy of the jaws

The aim of the present investigation was to three dimensionally assess craniofacial relationships in vivo. Specifically, by using a non‐invasive direct technique, the following measurements were made: 1) natural head position relative to the ground; 2) orientation of the occlusal plane relative to the subject's intrinsic facial planes; and 3) anteroposterior discrepancy of the dental bases, taking into consideration all the facial hard‐ and soft‐tissue structures. Several dental and soft‐tissue facial landmarks were directly digitized from 24 adult healthy volunteers with Angle Class I occlusions by means of an electromagnetic three‐dimensional computerized digitizer. In natural head position, the three‐dimensional orientation of Camper's, occlusal, and mandibular planes were measured along with the anteroposterior maxillo‐mandibular discrepancies. In the frontal plane projection, all the measured planes appeared about horizontal. In the lateral plane projection, on average, Camper's plane deviated from the true horizontal by approximately 18° (in a ‘head flexed’ direction). The occlusal plane deviated from the same horizontal by about 14°, while the mandibular plane had a steeper inclination (about 30°); both planes were significantly correlated to Camper's plane. The measurements of anteroposterior jaw discrepancy revealed a wide range of sagittal relationships in the analyzed subjects. The method was found to be repeatable and fast. This direct three‐dimensional in vivo assessment of the orientation of occlusal plane relative to the other facial planes could allow for a more comprehensive analysis of maxillo‐mandibular sagittal discrepancies.