Reversal of endogenous dopamine receptor silencing in pituitary cells augments receptor-mediated apoptosis

Dopamine (DA)-agonist targeting of the DA D(2) receptor (D2R) in prolactinomas is the first-line treatment choice for suppression of prolactin and induction of tumor shrinkage. Resistance to DA agonists seems to be related to receptor number. Using the MMQ and GH3 pituitary cell lines, that either do or do not express D2R, respectively, we explored the epigenetic profile associated with the presence or absence of D2R in these cells lines. These studies led us to explore pharmacological strategies designed to restore receptor expression and thereby potentially augment DA agonist-mediated apoptosis. We show in GH3 cells that the D2R harbors increased CpG island-associated methylation and enrichment for histone H3K27me3. Conversely, MMQ cells and normal pituitaries show enrichment for H3K9Ac and barely detectable H3K27me3. Coculture of GH3 cells with the demethylating agent zebularine and the histone deacetylase inhibitor trichostatin A was responsible for a decrease in CpG island methylation and enrichment for the histone H3K9Ac mark. In addition, challenge of GH3 cells with zebularine alone or coculture with both agents led to expression of endogenous D2R in these cells. Induced expression D2R in GH3 cells was associated with a significant increase in apoptosis indices to challenge with either DA or bromocriptine. Specificity of a receptor-mediated response was established in coincubations with specific D2R antagonist and siRNA approaches in GH3 cell and D2R expressing MMQ cell lines. These studies point to the potential efficacy of combined treatment with epigenetic drugs and DA agonists for the medical management of different pituitary tumor subtypes, resistant to conventional therapies.     

Objective methods to measure vestibular evoked myogenic potential response saccular tuning curves

Abstract

Objective: To detect cervical vestibular evoked myogenic potential (cVEMP) responses using objective statistical approaches and to apply this approach to estimate saccular frequency-tuning curves in volunteers and Ménière’s disease (MD) patients.

Design: Estimates of cVEMP threshold were carried out by 3 expert raters at 500?Hz and compared to objective threshold estimates (using Hotelling’s T² [HT²] and F_sp). Saccular tuning curves were objectively estimated.

Study sample: Objective and subjective estimates of cVEMP response thresholds were compared for 13 normal hearing adults. Objective measurement of saccular tuning curves was explored in 20 healthy adults and 15 patients with MD.

Results: Significant variability was seen between subjective estimates of cVEMP thresholds. Objective analysis with the HT² test was more sensitive than 2 of 3 experts in detecting responses. The measurement time of cVEMP was considerably reduced with the HT² test. Objective saccular tuning curves in volunteers showed strongest responses at 500?Hz. A flatter tuning curve was seen for MD patients.

Conclusions: There is significant variability in subjective estimations of cVEMP thresholds. Objective analysis methods are more sensitive than subjective analysis, can detect responses rapidly and have potential to reduce variability in threshold estimates, hence they appear well suited to measure cVEMP tuning curves.     

Recurrent giant hemangiomas of liver: Report of two rare cases with literature review

Most hepatic hemangiomas (HHs) are small, asymptomatic and do not require clinical intervention. Surgical resection is only indicated for symptomatic hemangiomas. We report here cases of recurrent HHs in 2 women of 37 and 40 years old, who initially presented with abdominal pain and mass. Radiological examination of each tumor revealed a solitary tumor of 14 and 20 cm in diameter, respectively. Surgical liver segmental resections were performed in both, and the diagnosis of cavernous hemangioma was confirmed. Both patients had recurrent tumor on subsequent radiological examination 4-5 years after the initial surgery. In the first patient, a 15 cm recurrent hemangioma was resected, but multiple hemangiomas were again detected 8 years later occupying the other hepatic lobe, which was not amendable for resection. In the second patient, a 16 cm hemangioma was seen on radiogram, and because the lesion was not symptomatic, conservative observation was offered. Recurrence after liver resection of giant hemangioma is extremely rare. The pathogenesis of tumor progression and recurrence is unknown, as is the management of these patients with recurrent hemangioma, particularly when it is extensive and unresectable.     

Mutation analysis of "Endoglin" and "Activin receptor-like kinase" genes in German patients with hereditary hemorrhagic telangiectasia and the value of rapid genotyping using an allele-specific PCR-technique

Background  

Hereditary hemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber syndrome, is an autosomal dominant disorder which is clinically characterised by recurrent epistaxis, mucocutaneous telangiectasia and visceral arteriovenous malformations. Genetic linkage studies identified two genes primarily related to HHT: endoglin (ENG) on chromosome 9q33-34 and activin receptor-like kinase1 (ACVRL1) on chromosome 12q13. We have screened a total of 41 unselected German patients with the suspected diagnosis of HHT. Mutation analysis for the ENG and ACVRL1 genes in all patients was performed by PCR amplification. Sequences were then compared to the HHT database sequences of the ENG mRNA (accession no. BC014271.2) and the ACVRL1 mRNA (accession no. NM000020.1).     

Consanguinity and Adverse Pregnancy Outcomes: The North of Jordan Experience

This cross-sectional study was carried out to assess the association between consanguineous marriages and adverse pregnancy outcome in the north of Jordan. Women delivered in four major hospitals in the north of Jordan between April 2007 and May 2007 were included in the study. Non-Jordanian women and women with multiple pregnancies were excluded. Mothers answered a pilot-tested structured questionnaire administered by trained personnel in the maternity ward. Data regarding pregnancy outcomes were obtained from the patients’ individual records. A total of 3,269 women with a mean age of 27.2 (SD 6.6) years were included. About 49% of women had consanguineous marriages. Consanguineous marriages were significantly associated with low birth weight delivery (13.9% vs. 10.1%), preterm delivery (19.9% vs. 12.3%), and births with congenital anomalies (4.1% vs. 0.8%) compared with non-consanguineous marriages. In the multivariate analysis, consanguinity was significantly associated with preterm delivery (OR = 1.5, 95% CI 1.2, 1.9), and congenital malformations (OR = 6.5, 95% CI 2.8, 15.3). In conclusions, this study supports the association between consanguinity and some adverse pregnancy outcomes.