Mutations in the PROP1 transcription factor gene lead to reduced production of thyrotropin, GH, prolactin, and gonadotropins as well as to pituitary hypoplasia in adult humans and mice. Some PROP1-deficient patients initially exhibit pituitary hyperplasia that resolves to hypoplasia. To understand this feature and to explore the mechanism whereby PROP1 regulates anterior pituitary gland growth, we carried out longitudinal studies in normal and Prop1-deficient dwarf mice from early embryogenesis through adulthood, examining the volume of Rathke's pouch and its derivatives, the position and number of dividing cells, the rate of apoptosis, and cell migration by pulse labeling. The results suggest that anterior pituitary progenitors normally leave the perilumenal region of Rathke's pouch and migrate to form the anterior lobe as they differentiate. Some of the cells that seed the anterior lobe during organogenesis have proliferative potential, supporting the expansion of the anterior lobe after birth. Prop1-deficient fetal pituitaries are dysmorphic because mutant cells are retained in the perilumenal area and fail to differentiate. After birth, mutant pituitaries exhibit enhanced apoptosis and reduced proliferation, apparently because the mutant anterior lobe is not seeded with progenitors. These studies suggest a mechanism for Prop1 action and an explanation for some of the clinical findings in human patients.

Mutations in the transcription factors PIT1 (pituitary transcription factor 1) and PROP1 (prophet of Pit1) lead to pituitary hormone deficiency and hypopituitarism in mice and humans. To determine the basis for this, we performed histological analysis of Pit1- and Prop1-deficient dwarf mouse pituitaries throughout fetal and postnatal development. Pit1-deficient mice first exhibit pituitary hypoplasia after birth, primarily caused by reduced cell proliferation, although there is some apoptosis. To determine whether altered development of the vascular system contributes to hypopituitarism, we examined vascularization from embryonic d 14.5 and throughout development. No obvious differences in vascularization are evident in developing Pit1-deficient pituitaries. In contrast, the Prop1-deficient mouse pituitaries are poorly vascularized and dysmorphic, with a striking elevation in apoptosis. At postnatal d 11, apoptosis-independent caspase-3 activation occurs in thyrotropes and somatotropes of normal but not mutant pituitaries. This suggests that Prop1 and/or Pit1 may be necessary for caspase-3 expression. These studies provide further insight as to the mechanisms of Prop1 and Pit1 action in mice.

ObjectThe authors compared the effectiveness of single-session (SS) and multisession (MS) stereotactic radiosurgery (SRS) for the treatment of spinal metastases.MethodsThe authors conducted a retrospective review of the clinical outcomes of 348 lesions in 228 patients treated with the CyberKnife radiosurgery at the University of Pittsburgh Cancer Institute and Georgetown University Medical Center. One hundred ninety-five lesions were treated using an SS treatment regimen (mean 16.3 Gy), whereas 153 lesions were treated using an MS approach (mean 20.6 Gy in 3 fractions, 23.8 Gy in 4 fractions, and 24.5 Gy in 5 fractions). The primary end point was pain control. Secondary end points included neurological deficit improvement, toxicity, local tumor control, need for retreatment, and overall survival.ResultsPain control was significantly improved in the SS group (SSG) for all measured time points up to 1 year posttreatment (100% vs 88%, p = 0.003). Rates of toxicity and neurological deficit improvement were not statistically different. Local tumor control was significantly better in the MS group (MSG) up to 2 years posttreatment (96% vs 70%, p = 0.001). Similarly, the need for retreatment was significantly lower in the MSG (1% vs 13%, p < 0.001). One-year overall survival was significantly greater in the MSG than the SSG (63% vs 46%, p = 0.002).ConclusionsSingle-session and MS SRS regimens are both effective in the treatment of spinal metastases. While an SS approach provides greater early pain control and equivalent toxicity, an MS approach achieves greater tumor control and less need for retreatment in long-term survivors.

Summary-We measured bone mineral density (BMD) in senior athletes competing in running and swimming events and compared results to those of sedentary controls. Total body BMD was greatest among runners suggesting that moderate impact activities continue to play a role in maintaining skeletal integrity with age.