Maternal exposures and risk of oral clefts in South Vietnam.

BACKGROUND: Oral clefts are among the most common congenital anomalies. Most studies on risk factors of oral clefts have been carried out in developed countries. We investigated the associations between maternal exposures in the first trimester and oral clefts in South Vietnam. METHODS: We conducted a hospital-based case-control study during October 2014-November 2015. Cases included 170 patients with nonsyndromic cleft lip with or without cleft palate and those with cleft palate only. Controls were 170 children without oral clefts, matched to each case by age and gender. Mothers were interviewed using structured questionnaire. We performed conditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Passive smoking was associated with increased risk of oral clefts in univariate analysis, but not in multivariable analysis (adjusted OR [aOR] = 1.68; 95% CI, 0.53-5.37). No association was observed between liver intake and oral clefts. Compared with nondrinkers, mothers who reported consumption of caffeine-containing beverages were more likely to have an infant with oral cleft (aOR = 5.89; 95% CI, 1.08-32.00). Periconceptional use of folic acid and multivitamins supplementation was associated with reduced risk of oral clefts (aOR = 0.01; 95% CI, 0.00-0.09 and aOR = 0.03; 95% CI, 0.01-0.13, respectively). CONCLUSIONS: The results suggest no associations of maternal passive smoking or liver intake with oral clefts. Periconceptional use of folic acid or multivitamins may protect against oral clefts. Further studies are warranted to examine the roles of caffeine consumption in pregnant mothers on occurrence of oral clefts in offspring.

Divergent cytotoxic effects of PKC412 in combination with conventional antileukemic agents in FLT3 mutation-positive versus -negative leukemia cell lines.

FMS-like tyrosine kinase-3 (FLT3) is a new therapeutic target for acute myelocytic leukemia (AML), because FLT3 mutations are the most common genetic alterations in AML and are directly related to leukemogenesis. We studied cytotoxic interactions of a FLT3 inhibitor, PKC412, with eight conventional antileukemic agents (cytarabine, doxorubicin, idarubicin, mitoxantrone, etoposide, 4-hydroperoxy-cyclophosphamide, methotrexate and vincristine) using three leukemia cell lines carrying FLT3 mutations (MOLM13, MOLM14 and MV4-11) and five leukemia cell lines without FLT3 mutations (KOPB-26, THP-1, BALL-1, KG-1 and U937). PKC412 showed synergistic effects with all agents studied except methotrexate for FLT3-mutated cell lines in isobologram analysis. In contrast, PKC412 was rather antagonistic to most drugs, except for 4-hydroperoxy-cyclophosphamide and vincristine, in leukemia cell lines without FLT3 mutations. Cell-cycle analysis revealed that PKC412 induced G1 arrest in leukemia cell lines carrying FLT3 mutations, whereas it arrested cells in G2/M phase in the absence of FLT3 mutations, which may underlie the divergent cytotoxic interactions. These results suggest that the simultaneous administration of PKC412 and other agents except methotrexate is clinically effective against FLT3 mutation-positive leukemias, whereas it would be of little benefit for FLT3 mutation-negative leukemias. Our findings may be of help for the design of PKC412-based combination chemotherapy.

FLT3 is fused to ETV6 in a myeloproliferative disorder with hypereosinophilia and a t(12;13)(p13;q12) translocation.

The FMS-like tyrosine kinase 3 (FLT3) gene, belonging to the receptor tyrosine kinase (TK) subclass III family, plays an important role in normal hematopoiesis and is one of the most frequently mutated genes in hematologic malignancies as well as an attractive target for directed inhibition. Activating mutations of this gene, including internal tandem duplication in the juxtamembrane (JM) domain and point mutations in the TK domain, are found in approximately one-third of patients with acute myeloid leukemia and in a smaller subset of patients with acute lymphoblastic leukemia. We report here that FLT3 may contribute to leukemogenesis in a patient with myeloproliferative disorder and a t(12;13)(p13;q12) translocation through generating a fusion gene with the ETS variant gene 6 (ETV6) gene. ETV6 has been reported to fuse to various partner genes, including TK and transcription factors. Both ETV6/FLT3 and reciprocal FLT3/ETV6 transcripts were detected in the patient mRNA by reverse transcriptase-polymerase chain reaction. At the protein level, however, only ETV6/FLT3 products were expressed. Among them, one retains the helix-loop-helix (HLH) oligomerization domain of ETV6 and the JM as well as TK domain of FLT3. FLT3 receptor in leukemic cells might be inappropriately activated through dimerization by HLH domain of ETV6, which consequently interfered with proliferation and differentiation of hematopoietic cells.

Factors predictive of attendance at clinic and blood pressure control in hypertensive patients.

Poor compliance with appointments and drug treatment is one of the recognised factors preventing effective management of hypertension. Factors predictive of poor attendance and inadequate blood pressure control in patients attending a hypertension clinic were therefore determined using univariate analyses and a multivariate logistic model. Out of 1346 patients with blood pressure exceeding 160/95 mm Hg followed up for three years, 209 (15.5%) dropped out during the first year. Variables that were significantly related to increased drop out rates were male sex, young age, obesity at entry, cigarette smoking, direct referral to the clinic as a result of screening instead of referral by a general practitioner, absence of pre-existing antihypertensive treatment at the first visit, moderate hypertension, and low socioeconomic category. Variables at entry that were significantly related to poor blood pressure control at one year were old age, evidence of coronary heart disease, severe hypertension, and raised blood glucose concentrations. Early detection of patients at high risk of drop out or poor blood pressure control might improve treatment of hypertension and allow management to be more individually adapted to each patient.