Retinal pericytes control expression of nitric oxide synthase and endothelin-1 in microvascular endothelial cells

Pericytes are known to communicate with endothelial cells by direct contact and by releasing cytokines such as TGF-beta. There is also strong evidence that pericytes act as regulators of endothelial cell proliferation and differentiation. We have investigated the effect of pericyte-conditioned medium (PCM) on proliferation of human microvascular endothelial cells in vitro, together with the expression of the vasoregulatory molecules, constitutive and inducible nitric oxide synthases (ecNOS and iNOS), and endothelin-1 (ET-1). Expression was measured at the mRNA level using semiquantitative RT-PCR for all three genes and at the protein level for ecNOS and iNOS using Western blotting. Growth curves for HMECs showed that PCM inhibits proliferation, eventually leading to cell death. Exposure to PCM repressed iNOS mRNA expression fivefold after 6 h. A similar, though delayed, reduction in protein levels was observed. ecNOS mRNA was slightly induced at 6 h, though there was no significant change in ecNOS protein. By contrast, ET-1 mRNA was induced 2.3-fold after 6 h exposure to PCM. We conclude that pericytes release a soluble factor or factors that are potent inhibitors of endothelial cell growth and promote vasoconstriction by up-regulating endothelin-1 and down-regulating iNOS. (C) 2000 Academic Press.

RUNX3 inactivation by frequent promoter hypermethylation and protein mislocalization constitute an early event in breast cancer progression

Background We had previously established that inactivation of RUNX3 occurs by frequent promoter hypermethylation and protein mislocalization in invasive ductal carcinomas (IDC) of breast. Here, we hypothesize that inactivation of RUNX3 occurring in ductal carcinoma in situ (DCIS) represent early event in breast carcinogenesis. Methods The study cohort of 40 patients included 17 pure DCIS cases and 23 cases of DCIS with associated IDC (DCIS-IDC). The DCIS and IDC components of mixed cases were manually microdissected to permit separate evaluation. All the 63 samples including 17 pure DCIS, 23 samples each of DCIS and IDC of DCIS-IDC cases were analyzed for RUNX3 protein expression using R3-6E9 monoclonal antibody as well as promoter methylation status by methylation specific PCR. Results Compared to matched normal breast samples (4 of 40, 10%), DCIS (35 of 40, 88%) and IDC (21 of 23, 91%) exhibited significant RUNX3 inactivation (P

Optimal glycaemic control, pre-eclampsia and gestational hypertension in women with type 1 diabetes in the Diabetes and Pre-Eclampsia Intervention Trial

OBJECTIVE
To assess the relationship between glycemic control, pre-eclampsia, and gestational hypertension in women with type 1 diabetes.

RESEARCH DESIGN AND METHODS
Pregnancy outcome (pre-eclampsia or gestational hypertension) was assessed prospectively in 749 women from the randomized controlled Diabetes and Pre-eclampsia Intervention Trial (DAPIT). HbA1c (A1C) values were available up to 6 months before pregnancy (n = 542), at the first antenatal visit (median 9 weeks) (n = 721), at 26 weeks’ gestation (n = 592), and at 34 weeks’ gestation (n = 519) and were categorized as optimal (<6.1%: referent), good (6.1–6.9%), moderate (7.0–7.9%), and poor (=8.0%) glycemic control, respectively.

RESULTS
Pre-eclampsia and gestational hypertension developed in 17 and 11% of pregnancies, respectively. Women who developed pre-eclampsia had significantly higher A1C values before and during pregnancy compared with women who did not develop pre-eclampsia (P < 0.05, respectively). In early pregnancy, A1C =8.0% was associated with a significantly increased risk of pre-eclampsia (odds ratio 3.68 [95% CI 1.17–11.6]) compared with optimal control. At 26 weeks’ gestation, A1C values =6.1% (good: 2.09 [1.03–4.21]; moderate: 3.20 [1.47–7.00]; and poor: 3.81 [1.30–11.1]) and at 34 weeks’ gestation A1C values =7.0% (moderate: 3.27 [1.31–8.20] and poor: 8.01 [2.04–31.5]) significantly increased the risk of pre-eclampsia compared with optimal control. The adjusted odds ratios for pre-eclampsia for each 1% decrement in A1C before pregnancy, at the first antenatal visit, at 26 weeks’ gestation, and at 34 weeks’ gestation were 0.88 (0.75–1.03), 0.75 (0.64–0.88), 0.57 (0.42–0.78), and 0.47 (0.31–0.70), respectively. Glycemic control was not significantly associated with gestational hypertension.

CONCLUSIONS
Women who developed pre-eclampsia had significantly higher A1C values before and during pregnancy. These data suggest that optimal glycemic control both early and throughout pregnancy may reduce the risk of pre-eclampsia in women with type 1 diabetes.

Gamma Knife Radiosurgery as a Therapeutic Strategy for Intracranial Sarcomatous Metastases

Purpose: To determine the indication and outcomes for Gamma Knife stereotactic radiosurgery (GKSRS) in the care of patients with intracranial sarcomatous metastases. Methods and Materials: Data from 21 patients who underwent radiosurgery for 60 sarcomatous intracranial metastases (54 parenchymal and 6 dural-based) were studied. Nine patients had radiosurgery for solitary tumors and 12 for multiple tumors. The primary pathology was metastatic leiomyosarcoma (4 patients), osteosarcoma (3 patients), soft-tissue sarcoma (5 patients), chondrosarcoma (2 patients), alveolar soft part sarcoma (2 patients), and rhabdomyosarcoma, Ewing's sarcoma, liposarcoma, neurofibrosarcoma, and synovial sarcoma (1 patient each). Twenty patients received multimodality management for their primary tumor, and 1 patient had no evidence of systemic disease. The mean tumor volume was 6.2 cm 3 (range, 0.07-40.9 cm 3), and a median margin dose of 16 Gy was administered. Three patients had progressive intracranial disease despite fractionated whole-brain radiotherapy before SRS. Results: A local tumor control rate of 88% was achieved (including patients receiving boost, up-front, and salvage SRS). New remote brain metastases developed in 7 patients (33%). The median survival after diagnosis of intracranial metastasis was 16 months, and the 1-year survival rate was 61%. Conclusions: Gamma Knife radiosurgery was a well-tolerated and initially effective therapy in the management of patients with sarcomatous intracranial metastases. However, many patients, including those who also received fractionated whole-brain radiotherapy, developed progressive new brain disease. © 2010 Elsevier Inc. All rights reserved.

Motor skill deficits in children with partial hearing

AIM:
We examined the effect of partial hearing, including cochlear implantation, on the development of motor skills in children (aged 6-12y).

METHOD:
Three independent groups of children were selected: a partial hearing group (n=25 [14 males, 11 females]; mean age 8y 8mo, SD 1y 10mo), a nonverbal IQ-matched group (n=27 [15 males, 12 females]; mean age 9y, SD 1y 6mo), and an age-matched group (n=26 [8 males, 18 females]; mean age 8y 8mo, SD 1y 7mo) from three schools with special units for children with partial hearing. All children with partial hearing had a bilateral hearing loss >60 decibels. Motor and balance skills were assessed using the Movement Assessment Battery for Children (MABC) and two protocols from the NeuroCom Balance Master clinical procedures.

RESULTS:
The mean standardized total MABC score of the children with partial hearing (95% confidence interval [CI] 71.8-88.7) was significantly lower than both the age-matched (95% CI 95.8-111.4; p<0.01) and the IQ-matched (95% CI 87.6-103.0; p=0.03) comparison groups. The children with partial hearing had particular difficulties with balance, most notably during tests of intersensory demand. However, subgroup analyses revealed that the effect of cochlear implantation was clearly dependent on the nature of the task.

INTERPRETATION:
Children with partial hearing are at high risk of clinical levels of motor deficit, with balance difficulties providing support for conventional vestibular deficit theory. However, the effect of cochlear implantation suggests that other sensory systems may be involved. A broader ecological perspective, which takes into account factors external to the child, may prove a useful framework for future research.

Confirmation of synthetic glucocorticoids with liquid chromatography/mass spectrometry: Organization and results of an international interlaboratory comparison test

Within the framework of a European Union (EU) research project entitled