The natural history of surgically treated but radiotherapy-naïve nonfunctioning pituitary adenomas

Background and objectives Transsphenoidal surgery is indicated for patients with nonfunctioning pituitary adenomas (NFPAs) causing compressive symptoms. Previous studies attempting to define the rate of recurrence/regrowth of surgically treated but radiation‐naïve NFPAs were somewhat limited by selection bias and/or small numbers and/or lack of consistency of findings between studies. A better understanding of the natural history of this condition could allow stratification of recurrence risk and inform future management. We aimed to define the natural history of a large, mainly unselected cohort with surgically treated, radiotherapy (RT)‐naïve NFPAs and to try to identify predictors of recurrence/regrowth. Design Case‐note analysis of all patients who underwent surgery for NFPA in our hospital between 1980 and 2006 was undertaken. Median follow‐up was 5·7 (range 1–25) years. Patients A total of 212 patients were identified of which 159 were suitable for analysis. 93% did not receive post‐operative RT. Measurement Post‐operative recurrent/regrowth was defined by any increase in tumour remnant size on serial post‐operative pituitary imaging. Results Recurrence/regrowth was documented in 53 patients (33·5%). Multivariate analysis revealed size of the post‐operative tumour remnant and length of follow‐up to be the two major determinants of recurrence/regrowth. The presence of a tumour with an extrasellar remnant was associated with the highest risk of recurrence (odds ratio 3·73 [CI: 1·97–7·09]), while no recurrence was seen in those with no residual tumour post‐operatively and regrowth risk was intermediate for those with remaining intrasellar remnant. Conclusion These results indicate that patients with post‐operative tumour with an extrasellar remnant should be considered routinely for adjuvant RT to reduce the risk of tumour regrowth while those with no residual tumour can be safely observed. Individualized decisions should be made for patients with an intrasellar remnant.     

MicroRNAs as prognostic indicators and therapeutic targets: potential effect on breast cancer management.

The discovery of microRNAs (miRNA) as novel modulators of gene expression has resulted in a rapidly expanding repertoire of molecules in this family, as reflected in the concomitant expansion of scientific literature. MiRNAs are a category of naturally occurring RNA molecules that play important regulatory roles in plants and animals by targeting mRNAs for cleavage or translational repression. Characteristically, miRNAs are noncoding, single-stranded short (18-22 nucleotides) RNAs, features which possibly explain why they had not been intensively investigated until recently. Accumulating experimental evidence indicates that miRNAs play a pivotal role in many cellular functions via the regulation of gene expression. Furthermore, their dysregulation and/or mutation has been shown in carcinogenesis. We provide a brief review of miRNA biogenesis and discuss the technical challenges of modifying experimental techniques to facilitate the identification and characterization of these small RNAs. MiRNA function and their involvement in malignancy, particularly their putative role as oncogenes or tumor suppressors is also discussed, with a specific emphasis on breast cancer. Finally, we comment on the potential role of miRNAs in breast cancer management, particularly in improving current prognostic tools and achieving the goal of individualized cancer treatment.     

Synapse replacement in the striatum of the adult rat following unilateral cortex ablation

Defining the selective pattern of synapse replacement that occurs in different areas of the damaged brain is essential for predicting the limits of functional compensation that can be achieved after various types of brain injury. Here we describe the time course of dendritic reorganization, spine loss and recovery, and synapse replacement in the striatum following a unilateral cortex ablation. We found that the time course for the transient loss and recovery of dendritic spines on medium spiny I (MSI) neurons, the primary postsynaptic target for corticostriatal axons, paralleled the time course for the removal of degenerating axon terminals from the neuropil and the formation of new synapses on MSI neurons. Reinnervation of the deafferented striatum occurred chiefly by axon terminals that formed asymmetric synapses with dendritic spines of MSI neurons, and the mean density of asymmetric synapses recovered to 86% of the sham-operated rat value by 30 days postlesion. In addition, the synaptic circuitry of the reconstructed striatum was characterized by an increase in the number of multiple synaptic boutons (MSBs), i.e., presynaptic axon terminals that make contact with more than one dendritic spine. Whether the postsynaptic contacts of MSBs are formed with the dendritic spines of the same or a different parent dendrite in the striatum is unknown. Nevertheless, these data suggest that the formation of MSBs is an essential part of the compensatory response to the loss of input from the ipsilateral cortex following the aspiration lesion and may serve to modulate activity-dependent adaptive changes in the reconstructed striatum that can lead to functional recovery.     

Association between bone lead concentration and blood pressure among young adults

BACKGROUND: Occupational and environmental exposure to lead has been examined for its effect on blood pressure (BP) in adults with varying results. The present analyses assessed the association between bone lead concentration and BP in early adult life in persons exposed during childhood. METHODS: Study participants included young adult members of two cohorts with different past histories of lead exposure. Lead exposure was assessed using noninvasive K-X-ray fluorescence spectroscopy to quantify bone lead concentration, an index of long-term lead exposure superior to current blood lead concentration. Systolic and diastolic BP measurements were obtained using conventional clinical methods. Multiple linear regression models were constructed to allow for control of covariates of BP identified a priori. RESULTS: Analyses were performed on 508 participants. While controlling for potential confounders, systolic BP was 4.3 mm Hg greater among members of the highest of four bone lead concentration groups (> 10 microg Pb/g bone) when compared with the lowest bone lead concentration group (< 1 microg Pb/g bone; P = 0.004), and diastolic BP was 2.8 mm Hg greater among members of the highest bone lead concentration group when compared with the lowest bone lead concentration group (P = 0.03). CONCLUSIONS: These results suggest that substantial lead exposure during childhood can increase BP during young adulthood.     

Chronic thromboxane synthase inhibition prevents fructose-induced hypertension

To investigate the role of thromboxane A(2) in the development of hypertension in the fructose-fed rat, we treated male fructose-fed rats with dazmegrel (a thromboxane synthase inhibitor) and monitored blood pressure, fasting plasma parameters, and insulin sensitivity for 7 weeks. Systolic blood pressure was measured each week using tail plethysmography, and an oral glucose tolerance test was performed at the end of the study to assess insulin sensitivity. Treatment with a 60% fructose diet and dazmegrel (100 mg. kg(-1). d(-1) via oral gavage) was initiated on the same day. Plasma triglyceride levels increased 2-fold in both fructose- and fructose/dazmegrel-treated groups, and plasma insulin levels tended to be higher in these groups, although not significantly. Systolic blood pressure increased significantly throughout the study in the fructose-fed group only (132+/-3 versus 112+/-4 mm Hg in control rats, 118+/-2 mm Hg in control-treated rats, 116+/-2 mm Hg in fructose-treated rats). Both fructose groups demonstrated a higher peak insulin response to oral glucose challenge and had 40% to 60% lower insulin sensitivity index values. The results of this study show that treatment with a thromboxane synthase inhibitor, dazmegrel, can prevent the development of hypertension but does not improve insulin sensitivity or other fructose-induced metabolic impairments. Based on these data, we conclude that the potent vasoconstrictor thromboxane is involved in the link between hyperinsulinemia/insulin resistance and hypertension.