Differential sclerostin and parathyroid hormone response to exercise in boys and men.

SUMMARY: Physical exercise benefits bone structure and mineralization, especially in children. Immediately following high-impact exercise, PTH increased and returned to resting values within 24 h in both groups, while sclerostin increased in men but not in boys. The underlying mechanisms and implication of this age-related differential response are unclear. INTRODUCTION: Circulating sclerostin, a negative regulator of bone, decreases during puberty and increases in adulthood. Parathyroid hormone (PTH) is inversely related to sclerostin. In mice, sclerostin decreases following 24 h of mechanical stimulation. Its response to exercise in humans and, especially in children, in whom high-impact physical exercise benefits bone structure and mineralization is unclear. The aim of this study was to investigate the acute response of sclerostin to a single exercise session of high mechanical loading and the corresponding changes in PTH in boys and men. METHODS: Twelve boys (10.2 ± 0.4 years old) and 17 young men (22.7 ± 0.8 years old) underwent a protocol of plyometric exercises (total 144 jumps). Blood samples were collected pre-, 5 min, 1 h, and 24 h post-exercise. RESULTS: Boys had significantly higher resting values of sclerostin compared with men (150 ± 37 vs. 111 ± 34 pg/ml, respectively, p = 0.006). Following exercise, sclerostin markedly increased in men but this response was attenuated in boys (at 5 min: 51 ± 38 vs. 14 ± 21%, respectively, p = 0.005). PTH levels were similar in boys and men at rest and throughout the 24-h study period, increasing significantly (p < 0.001) 5 min after exercise, decreasing after 60 min post-exercise and returning to resting values within 24 h. CONCLUSION: Although the PTH response was similar in boys and men, the sclerostin response was greater in men. The combined increases in PTH and sclerostin immediately post-exercise appear contrary to the accepted osteogenic effect of exercise. The underlying mechanisms and full implication of the differential response between children and adults need to be further examined.

Xanthoma disseminatum of the central nervous system and cranium.

Xanthoma disseminatum is a rare normolipemic histiocytic disorder of non-Langerhans cell origin. It is a chronic systemic disease with a benign course, characterized by disseminated, yellow-orange-colored papules on the face, flexures, and mucosal membranes. We report 3 patients with xanthoma disseminatum, who presented primarily with central nervous system disease and a multitude of imaging findings throughout the craniospinal axis.

Crystallographic structures of the ligand-binding domains of the androgen receptor and its T877A mutant complexed with the natural agonist dihydrotestosterone.

The structures of the ligand-binding domains (LBD) of the wild-type androgen receptor (AR) and the T877A mutant corresponding to that in LNCaP cells, both bound to dihydrotestosterone, have been refined at 2.0 A resolution. In contrast to the homodimer seen in the retinoid-X receptor and estrogen receptor LBD structures, the AR LBD is monomeric, possibly because of the extended C terminus of AR, which lies in a groove at the dimerization interface. Binding of the natural ligand dihydrotestosterone by the mutant LBD involves interactions with the same residues as in the wild-type receptor, with the exception of the side chain of threonine 877, which is an alanine residue in the mutant. This structural difference in the binding pocket can explain the ability of the mutant AR found in LNCaP cells (T877A) to accommodate progesterone and other ligands that the wild-type receptor cannot.

Rate of PSA rise predicts metastatic versus local recurrence after definitive radiotherapy.

OBJECTIVE: A rising prostate specific antigen (PSA) following treatment for adenocarcinoma of the prostate indicates eventual clinical failure, but the rate of rise can be quite different from patient to patient, as can the pattern of clinical failure. We sought to determine whether the rate of PSA rise could differentiate future local versus metastatic failure. METHODS AND MATERIALS: Two thousand six hundred sixty-seven PSA values from 400 patients treated with radiotherapy for localized adenocarcinoma of the prostate were analyzed with respect to PSA patterns and clinical outcome. Patients had received no hormonal therapy or prostate surgery and had > 4 PSA values post-treatment. PSA rate of rise, determined by the slope of the natural log, was classified as gradual [< 0.69 log(ng/ml)/year, or doubling time (DT) > 1 year], moderate [0.69-1.4 log(ng/ml)/year, or DT 6 months-1 year], or rapid [> 1.4 log(ng/ml)/year, or DT < 6 months]. RESULTS: Sixty-one percent of patients had non-rising PSA following treatment; 25% of patients with rising PSA developed clinical failure, and 93% of patients with clinical failure had rising PSA. The rate of rise discerned different clinical failure patterns. Local failure occurred in 23% of patients with moderate rate of rise versus 7% with gradual rise (p = 0.0001). Metastatic disease developed in 46% of those with rapid rise versus 8% with moderate rise (p < 0.0001). By multivariate analysis, in addition to rate of rise, PSA nadir and rate of decline predicted local failure; those with post-treatment nadir of 1-4 ng/ml were five times more likely to experience local failure than nadir < 1 ng/ml (p = 0.0002). Rapid rate of rise was the most significant independent predictor of metastatic failure. CONCLUSIONS: The rate of PSA rise following definitive radiotherapy can predict clinical failure patterns, with a rapidly rising PSA indicating metastatic recurrence and moderately rising PSA local recurrence. This information could potentially direct therapy; if the rise predicts metastatic failure hormonal therapy could be considered, while aggressive salvage therapy may benefit subclinical local recurrence identified by a moderate rate of PSA rise.

Results of 3D conformal radiotherapy in the treatment of localized prostate cancer.

PURPOSE: 3D conformal radiotherapy (3D CRT) has been shown to decrease acute morbidity in the treatment of prostate cancer. Therapeutic outcome and late morbidity data have been accumulating. To evaluate the results of 3D CRT for the treatment of prostate cancer, we analyzed the outcome of a large series of patients treated with conformal techniques. MATERIAL AND METHODS: From January 1987 through June 1994, 707 patients with localized prostate cancer were treated with 3D CRT. Patients with pathologically-confirmed pelvic lymph node metastasis, treated with pre-irradiation (preRT) androgen ablation, or treated post-prostatectomy were excluded. All had CT obtained specifically for treatment planning, multiple structures contoured on the axial images, and beam's-eye view conformal beams edited to provide 3D dose coverage. Median follow-up is 36 mos; 70 patients have been followed longer than 5.5 years. Six hundred three had T1-T2 tumors. PreRT prostate specific antigen (PSA) was available for 649 patients: median preRT PSA was 12.9 ng/ml, 209 patients had preRT PSA > 20 ng/ml. The median dose of radiation was 69 Gy; 102 patients received > or = 69 Gy. Biochemical failure was defined as: 1) two consecutive PSA rises over 2.0 ng/ml if nadir PSA < or = 2.0 ng/ml, 2) two consecutive PSA rises over nadir if nadir PSA > 2.0 ng/ml, or 3) initiation of hormonal therapy after RT. Complications were graded using the RTOG system. RESULTS: PreRT PSA and Gleason score emerged as independent indicators of biochemical control (bNED). Patients with preRT PSA > 10 had a significantly worse bNED at 5 years than patients with preRT PSA < or = 10. Five-year bNED was determined according to preRT PSA: PSA < or = 4, 88%; PSA > 4 < or = 10, 72%; PSA > 10 < or = 20, 43%; and PSA > 20, 30%. Patients with Gleason score > or = 7 also had a significantly worse bNED than patients with Gleason score < 7. Patients were divided into two prognostic groups: a favorable group with PSA < or = 10, Gleason score < 7, and T1-T2 tumors, and an unfavorable group with PSA > 10, Gleason score > or = 7 or T3-T4 tumors and studied for the effect of dose on bNED status. The bNED at 5 years was 75% for the favorable group and 37% for the unfavorable group. In addition, a group that might be considered a surgical subset was reviewed: patients with PSA < or = 10, Gleason score < or = 7, and T1-T2 tumors who were < 70 years old. This subset had an 84% 5-year bNED rate and 98% 5-year overall survival. Complications with the techniques used here are very low: 3% risk at 7 years of Grade 3-4 complications and 1% risk at 7 years of Grade 3 bladder complications (no Grade 4). CONCLUSION: 3D CRT allows for treatment of prostate cancers with a very low risk of complications. Patients with relatively early disease as defined by preRT PSA, Gleason score < 7, and T1-2 tumors and patients who are candidates for radical prostatectomy have excellent 5-year bNED rates. Patients with adverse prognostic factors have a high risk of biochemical recurrence and are candidates for innovative therapy.

Histopathologic effects of transarterial bucrylate occlusion of intracerebral arteries in mongrel dogs.

Bucrylate was injected directly into the cerebral cortical arteries of mongrel dogs. Preparations for light and electron microscopy were obtained from 5 min to 5 months after the introduction of the polymer. A mixed pattern of damage to arterial endothelium was seen, including electron microscopic documentation of stripping away of the endothelium. Acute effects include a subocclusive thrombogenic matrix, which causes partial or complete thrombosis. The long-term reactions are those of a chronic inflammatory response to a foreign body.