Endocrine disruption in human placenta: expression of the dioxin-inducible enzyme, CYP1A1, is correlated with that of thyroid hormone-regulated genes.

CONTEXT: Thyroid hormone (TH) is essential for normal development; therefore, disruption of TH action by a number of industrial chemicals is critical to identify. Several chemicals including polychlorinated biphenyls are metabolized by the dioxin-inducible enzyme CYP1A1; some of their metabolites can interact with the TH receptor. In animals, this mechanism is reflected by a strong correlation between the expression of CYP1A1 mRNA and TH-regulated mRNAs. If this mechanism occurs in humans, we expect that CYP1A1 expression will be positively correlated with the expression of genes regulated by TH. OBJECTIVE: The objective of the study was to test the hypothesis that CYP1A1 mRNA expression is correlated with TH-regulated mRNAs in human placenta. METHODS: One hundred sixty-four placental samples from pregnancies with no thyroid disease were obtained from the GESTE study (Sherbrooke, Québec, Canada). Maternal and cord blood TH levels were measured at birth. The mRNA levels of CYP1A1 and placental TH receptor targets [placental lactogen (PL) and GH-V] were quantitated by quantitative PCR. RESULTS: CYP1A1 mRNA abundance varied 5-fold across 132 placental samples that had detectable CYP1A1 mRNA. CYP1A1 mRNA was positively correlated with PL (r = 0.64; P < .0001) and GH-V (P < .0001, r = 0.62) mRNA. PL and GH-V mRNA were correlated with each other (r = 0.95; P < .0001), suggesting a common activator. The mRNAs not regulated by TH were not correlated with CYP1A1 expression. CONCLUSIONS: CYP1A1 mRNA expression is strongly associated with the expression of TH-regulated target gene mRNAs in human placenta, consistent with the endocrine-disrupting action of metabolites produced by CYP1A1.

Luteoma of pregnancy associated with nearly complete virilization of genetically female twins.

OBJECTIVE: To describe a pregnancy that was complicated by the virilization of the mother and two 46XX infants. METHODS: We outline the clinical presentation and diagnosis of the virilization of a mother and her twins, reviewing pertinent literature. RESULTS: We report the case of a 40-year-old Caucasian female who conceived a trichorionic triplet pregnancy through in vitro fertilization (IVF) but underwent cytoreduction at 13 weeks of gestation, leaving a diamniotic dichorionic twin pregnancy. At 16 weeks of gestation the mother experienced increasing acne, facial hair, and deepening of her voice. Due to preeclampsia, the twins were delivered via caesarean section at 33 weeks of gestation. The infants had male-appearing external genitalia (Prader score IV-V) but no palpable gonads. Congenital adrenal hyperplasia was ruled out for both twins and they were both found to have a uterus and a 46XX karyotype. Maternal testosterone level was elevated at birth (1,981 ng/dL), but the infants had normal levels. Maternal testosterone levels returned to normal after delivery, consistent with a luteoma of pregnancy, although imaging was negative for a mass. CONCLUSION: This is the second reported case of complete virilization associated with a luteoma of pregnancy. Whether or not IVF and related procedures increase the risk for a luteoma and whether or not fetal reduction procedures disrupt placental aromatases and increase the risk of virilization in the face of elevated androgen levels are questions that require further research.

Site of initial diabetes education does not affect metabolic outcomes in children with T1DM.

OBJECTIVE: To determine the difference in metabolic outcomes at 1 and 2 yr post type 1 diabetes mellitus (T1DM) diagnosis in children depending on the site of initial diabetes education: inpatient, vs. outpatient, vs. mixed locations. PATIENTS AND METHODS: A retrospective chart review was performed for all patients with new onset antibody positive T1DM, aged 1-18 yr old, diagnosed in 2004-2009, and followed for at least 1 yr in a diabetes program at a tertiary academic health care center. Patients were divided into three groups based on the site of initial diabetes education: inpatient, outpatient, and mixed locations. The primary outcome was A1c at 1 and 2 yr. RESULTS: We enrolled 238 children (133 boys), mean (± SD) age 9.9 (± 4.1). A1c levels did not differ among inpatient, outpatient, and mixed location groups at 1 and 2 yr post diagnosis (p = 0.85 and p = 0.69, respectively) and the long-acting insulin doses were similar at 1 and 2 yr (p = 0.18 and p = 0.15, respectively). There was no difference in the number of acute diabetes complications between the groups. At 1 yr, 21.8% of outpatient-educated children were on insulin pump therapy in contrast to 14.7% of inpatient and 2.7% of mixed educated groups (p = 0.04). CONCLUSIONS: Families of children with new onset T1DM can be successfully and safely educated in a clinic setting. An 'education' admission for a medically stable patient is not necessary most of the time, however, clinical judgment and careful assessment of the family's coping and learning capabilities are important when determining the site of education.

Dynein light intermediate chain 1 is required for progress through the spindle assembly checkpoint.

The spindle assembly checkpoint monitors microtubule attachment to kinetochores and tension across sister kinetochores to ensure accurate division of chromosomes between daughter cells. Cytoplasmic dynein functions in the checkpoint, apparently by moving critical checkpoint components off kinetochores. The dynein subunit required for this function is unknown. Here we show that human cells depleted of dynein light intermediate chain 1 (LIC1) delay in metaphase with increased interkinetochore distances; dynein remains intact, localised and functional. The checkpoint proteins Mad1/2 and Zw10 localise to kinetochores under full tension, whereas BubR1 is diminished at kinetochores. Metaphase delay and increased interkinetochore distances are suppressed by depletion of Mad1, Mad2 or BubR1 or by re-expression of wtLIC1 or a Cdk1 site phosphomimetic LIC1 mutant, but not Cdk1-phosphorylation-deficient LIC1. When the checkpoint is activated by microtubule depolymerisation, Mad1/2 and BubR1 localise to kinetochores. We conclude that a Cdk1 phosphorylated form of LIC1 is required to remove Mad1/2 and Zw10 but not BubR1 from kinetochores during spindle assembly checkpoint silencing.