Substituting human chorionic gonadotropin by gonadotropin-releasing hormone agonist to trigger final follicular maturation, during controlled ovarian hyperstimulation, results in less systemic inflammation.

BACKGROUND: To investigate the degree of systemic inflammation, as reflected by serum C-reactive protein (CRP) levels, associated with controlled ovarian hyperstimulation (COH) with human chorionic gonadotropin (hCG) or gonadotropin-releasing hormone (GnRH) agonist for the induction of final follicular maturation. DESIGN: Prospective, observational study. SETTING: An in vitro fertilization (IVF) unit of an academic medical center. PATIENTS: Twenty-four women undergoing COH and IVF with the flexible GnRH antagonist protocol were prospectively assigned to receive hCG or GnRH agonist for the induction of final follicular maturation. METHODS: Blood was drawn three times during COH for measurement of sex-steroid and CRP levels: the day on which adequate suppression was obtained (Day-0); the day of or prior to administration of hCG (Day-hCG); and (3) the day of ovum pick-up (Day-OPU). Levels were compared among the three time points in the two groups. RESULTS: No between-group differences were observed in terms of patient age, gonadotropin dosage, duration of stimulation or number of oocytes retrieved. Serum CRP levels were significantly higher on Day-OPU than on Day-hCG and Day-0, but the difference was significant only in the hCG group (p<0.03 for both). The percentage change in CRP levels after hCG administration (Day-OPU vs. Day-hCG) (96%) was higher than that after GnRH administration (23%). CONCLUSION: Administration of GnRH agonist in patients undergoing COH for IVF yields a lesser degree of systemic inflammation, as reflected by CRP levels, than hCG.     

Effects of pegfilgrastim on normal biodistribution of 18F-FDG: preclinical and clinical studies.

The purpose of this study was to evaluate the effects of pegfilgrastim, a long-acting granulocyte colony-stimulating factor, on the normal biodistribution of (18)F-FDG in an animal model and in humans. METHODS: Two groups of 12 rats received a single subcutaneous injection of either normal saline or pegfilgrastim. One, 7, 14, and 21 d after injection, biodistribution studies were performed 1 h after (18)F-FDG injection. Sixteen breast cancer patients underwent baseline (18)F-FDG PET/CT and, approximately 1 wk after receiving 1 dose of docetaxel and adjunctive pegfilgrastim, follow-up (18)F-FDG PET/CT (scan 2). Standardized uptake values corrected for lean body mass (SUL) were determined for several normal organs before and after therapy. RESULTS: In rats, bone marrow (18)F-FDG uptake (standardized uptake value) was higher in the pegfilgrastim group 1 d after injection (mean +/- SD, 8.3 +/- 4.1 vs. 2.5 +/- 0.2, P < 0.05), whereas (18)F-FDG uptake in blood was lower (0.41 +/- 0.06 vs. 0.49 +/- 0.01, P < 0.05). In patients, mean SUL was higher in bone marrow (4.49 +/- 1.50 vs. 1.33 +/- 0.22, P < 0.0001), spleen (3.29 +/- 0.83 vs. 1.23 +/- 0.23, P < 0.0001), and liver (1.45 +/- 0.25 vs. 1.31 +/- 0.23, P = 0.01) but lower in brain (4.18 +/- 0.76 vs. 5.14 +/- 1.44, P < 0.01) on scan 2 than on the baseline scan. CONCLUSION: In both the animal model and humans, pegfilgrastim markedly increased bone marrow uptake of (18)F-FDG and reduced (18)F-FDG uptake in some normal tissues. These profound alterations in (18)F-FDG biodistribution induced by pegfilgrastim must be considered when one is evaluating quantitative (18)F-FDG PET scans for tumor response to therapy.     

Toll-like receptor 9 ligand blocks osteoclast differentiation through induction of phosphatase.

CpG-ODN, in addition to stimulation of osteoclastogenic signals in early osteoclast precursors, also induces phosphatase, shifting the pattern of ERK phosphorylation from sustained to transient. This shift results in the degradation of c-fos, an essential molecule for osteoclast differentiation. Therefore, CpG-ODN blocks osteoclast differentiation. INTRODUCTION: Activation of either Toll-like receptor 9 (TLR9) or RANK induces similar responses in osteoclast precursors. Paradoxically, activation of TLR9 results in inhibition of RANKL-induced osteoclastogenesis. MATERIALS AND METHODS: We used bone marrow-derived osteoclast precursors. Analyses of signaling molecules phosphorylation were performed using Western blotting. Different levels of gene expression analyses were performed using RT-PCR, Northern, and run-on analyses (for RNA), and EMSA, Western, and pulse-chase experiments (for protein). Phosphatase activity was measured spectrophotometrically. RESULTS: We found that RANKL and TLR9 ligand, oligodeoxynucleotides containing unmethylated CpG dinucleotides (CpG-ODN), induce sustained and transient extracellular signal-regulated kinase (ERK) phosphorylation, respectively. Furthermore, together they induce a transient phosphorylation of ERK. The duration of ERK phosphorylation is a key factor in determining induction of c-fos, a protein critical for osteoclastogenesis. Indeed, we found that CpG-ODN does not induce c-fos and inhibits its induction by RANKL by enhancing c-fos mRNA and protein degradation. Our observation that CpG-ODN, but not RANKL, induces the expression of the phosphatase PP2A suggests that CpG-ODN exerts its inhibitory activity by induction of ERK dephosphorylation. Moreover, together with the phosphatase inhibitor okadaic acid, CpG-ODN induces sustained ERK phosphorylation and c-fos expression. CONCLUSIONS: Our findings suggest that the increased rate of c-fos degradation by the TLR9 ligand mediates the inhibition of RANKL-induced osteoclast differentiation. The TLR9 ligand, through induction of dephosphorylation, prevents the sustained ERK phosphorylation needed for maintaining high c-fos levels that are essential for osteoclast differentiation.     

Better, (perhaps) cheaper, but is it best?

Patients presented at the emergency room with chest pain, non-characteristicECG changes and negative Troponin represent a very frequentclinical dilemma. These patients are often hospitalized unnecessarilyand frequently undergo non-invasive and even invasive investigationswhich turn out to be negative. Occasionally, they may falselybe discharged from the ER and eventually develop a major cardiacevent. The most common and apparently the cheapest test employedin the evaluation of these patients is standard exercise ECG.Jeetley et al.¹ prospectively studied a large group ofsuch patients. The patients     

Real-time refinement of subthalamic nucleus targeting using Bayesian decision-making on the root mean square measure.

The subthalamic nucleus (STN) is a major target for treatment of advanced Parkinson's disease patients undergoing deep brain stimulation surgery. Microelectrode recording (MER) is used in many cases to identify the target nucleus. A real-time procedure for identifying the entry and exit points of the STN would improve the outcome of this targeting procedure. We used the normalized root mean square (NRMS) of a short (5 seconds) MER sampled signal and the estimated anatomical distance to target (EDT) as the basis for this procedure. Electrode tip location was defined intraoperatively by an expert neurophysiologist to be before, within, or after the STN. Data from 46 trajectories of 27 patients were used to calculate the Bayesian posterior probability of being in each of these locations, given RMS-EDT pair values. We tested our predictions on each trajectory using a bootstrapping technique, with the rest of the trajectories serving as a training set and found the error in predicting the STN entry to be (mean +/- SD) 0.18 +/- 0.84, and 0.50 +/- 0.59 mm for STN exit point, which yields a 0.30 +/- 0.28 mm deviation from the expert's target center. The simplicity and computational ease of RMS calculation, its spike sorting-independent nature and tolerance to electrode parameters of this Bayesian predictor, can lead directly to the development of a fully automated intraoperative physiological procedure for the refinement of imaging estimates of STN borders.     

Postural stability by computerized posturography in minor head trauma

Mild head injuries are very common among young children. Often, these injuries are followed by a variety of subjective complaints termed posttraumatic syndrome. Posturography (balance test) was performed immediately after the trauma in 21 children who had sustained mild head injury. Significant difference in performance was observed in head-injured children in all subparts of the test as compared with a control group. We conclude that posturography may serve as a simple cost-effective method in qualifying the posttraumatic imbalance.     

25-Hydroxyvitamin D3 metabolism in a human leukemia cell line

Summary 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃) is a potent inducer of monocytic differentiation of the human promyelocytic leukemia cell line, HL-60. We have noted that 25-hydroxyvitamin D₃ (25(OH)D₃) in high doses is also capable of promoting monocytic differentiation of this cell line. To test the possibility that the latter activity is due to conversion of 25OHD₃ to 1,25(OH)₂D₃ by HL-60, we exposed HL-60 cells to 25OHD₃ and analyzed the products by HPLC and radioreceptor assay. When chromatographed in the traditional solvent system (isopropanol-hexane), a new peak appears which migrates with authentic 1,25(OH)₂D₃. However, in a solvent system containing dichloromethane, 90% of the peak migrates with another metabolite, 19-Nor-10-Keto-25OHD₃ (19-Nor-25OHD₃). Production of this metabolite is enhanced by living cells and is synthesized by both virgin HL-60 and those which have undergone differentiation. We next determined if authentic 19-Nor-25OHD₃ also promotes differentiation of this cell. As assessed by appearance of the monocyte-specific surface antigen (63D3) and macrophage-specific esterase activity, we find that this metabolite does, in fact, induce monocytic differentiation of HL-60 with a potency of approximately 1/200 that of 1,25(OH)₂D₃ and similar to that of 25OHD₃. In agreement with the effect upon cell maturation, 19-Nor-25OHD₃ displaces³H-1,25(OH)₂D₃ from its HL-60 receptor with an efficiency comparable to 25OHD₃. Hence, HL-60 cells convert 25OHD₃ to 19-Nor-25OHD₃, and 19-Nor-25OHD₃ induces monocytic differentiation of HL-60 with comparable efficiency to its precursor, 25OHD₃.