The effect of contrast dose,imaging time,and lesion size in the MR detection of intracerebral metastasis.

PURPOSETo evaluate the effect of MR contrast dose versus delayed imaging time on the detection of metastatic brain lesions based on lesion size.METHODSContrast MR examinations with gadoteridol were obtained in 45 patients with brain metastases. The patients were divided into two groups: 16 received cumulative standard dose (0.1 mmol/kg) and 29 received cumulative triple dose (0.3 mmol/kg). Both groups were evaluated at two dose levels (lower dose and higher dose) with two separate injections. Each patient received an initial bolus injection of either 0.05 (cumulative standard dose) or 0.1 (cumulative triple dose) mmol/kg of gadoteridol to reach the lower-dose level and underwent imaging immediately and 10 and 20 minutes later. Thirty minutes after injection, an additional bolus injection of 0.05 (cumulative standard dose) or 0.2 (cumulative triple dose) mmol/kg was administered to reach the cumulative higher-dose level (cumulative standard dose, 0.1 mmol/kg; cumulative triple dose, 0.3 mmol). Images were acquired immediately.RESULTSThere was no difference in the detection rate for lesions larger than 10 mm among T2-weighted, lower-dose immediate and delayed, or immediate higher-dose images in both study groups. Lesions smaller than 10 mm had improved detection with delayed imaging in both study groups; however, the immediate higher-dose studies still had the highest detection rate.CONCLUSIONIn the evaluation of small central nervous system metastases, either delayed imaging after the injection of standard contrast dose or higher contrast dose may improve their detection, and therefore affect clinical management. Higher contrast dose (cumulative triple dose) studies appear to be more effective than delayed imaging with standard dose.     

Cardiovascular effects of caffeine and nifedipine

Because caffeine and nifedipine may have opposing effects on intracellular calcium concentration, a possible interaction between these agents on blood pressure and heart rate was examined. With a randomized, double-blind, crossover design, 10 normal, caffeine-abstaining subjects received caffeine, 300 mg, or placebo followed by nifedipine, 10 mg, or placebo. Caffeine increased blood pressure, whereas nifedipine reduced it and caused a reflex increase in heart rate. With caffeine pretreatment, nifedipine decreased blood pressure significantly more than with placebo pretreatment. However, nifedipine reduced blood pressure to the same absolute level on both the caffeine and placebo pretreatment days. The reflex increase in heart rate after nifedipine was not affected by prior caffeine or placebo administration. Caffeine pretreatment does not alter the cardiovascular responses to nifedipine but the pressor effect of caffeine is completely reversed by subsequent nifedipine administration.     

Importance of Albumin, 25(OH)-Vitamin D and IGFBP-3 as Risk Factors in Elderly Women and Men with Hip Fracture

The relative importance of vitamin D deficiency, secondary hyperparathyroidism, nutritional deficiency and low bone mineral density (BMD) as risk factors for hip fracture is not definitely established. In the framework of a case-control study of risk factors for hip fractured, biochemical markers of bone metabolism and nutrition and femoral BMD data were compared in 136 female and 43 male hip fracture patients, 126 female and 44 male age-matched hospitalized controls, and 47 healthy elderly women (8 men). Patients with hip fracture had lower albumin (−10%9 and 25(OH)-vitamin D (25(OH)D; −19%) compared with hospitalized controls, and lower albumin (−28%) and 25(OH)D levels (−52%) compared with the elderly controls. Serum values of IGFBP-3 were also significantly lower (−33%) in hip fracture patients than in community controls. BMD of femoral neck was lower (p < 0.001) in patients than in hospitalized and community controls. In hip fracture patients, parathyroid hormone (PTH) correlated weakly with BMD (neck: r = −0.19, trochanter: r = −0.17; both p < 0.05). When all women were pooled (n = 233), albumin correlated significantly (age-adjusted) with BMD at all sites (neck: r = 0.27, trochanter: r = 0.25; all p < 0.001). Albumin, but not 25(OH)D, also correlated with skinfold thickness (r = 0.19, p < 0.0025) and with body mass index (BMI) (r = 0.14, p < 0.05). Male patients with hip fracture had lower BMD and albumin (both p < 0.001), 25(OH)D (p = 0.02) and IGFBP-3 levels (p <: 0.005) compared with the controls. When male patients and controls were pooled together, albumin, skinfold thickness and BMI were significantly correlated with each other, but not with BMD. IGFBP-3 was highly correlated with albumin (p < 0.0001), 25(OH)D (p < 0.005) and, less significantly, with PTH (p < 0.05), but not with BMI or skinfold thickness. IGFBP-3 was significantly correlated with BMD at all sites (neck: r = 0.27, p < 0.05); trochanter: r = 0.40, p < 0.0005). In conclusion, low albumin and low BMD were both important risk factors for hip fracture. Low serum albumin was the strongest independent variable correlated with hip fractures. In men, IGFBP-3 was correlated with BMD. The femoral BMD depended only weakly on PTH and 25(OH)D, but was correlated at all sites with albumin, a non-specific parameter of nutrition and general health.     

A tracer kinetic model for 18F-FHBG for quantitating herpes simplex virus type 1 thymidine kinase reporter gene expression in living animals using PET.

Reporter probe 9-(4-18F-fluoro-3-[hydroxymethyl]butyl)guanine (18F-FHBG) and reporter gene mutant herpes simplex virus type 1 thymidine kinase (HSV1-sr39tk) have been used for imaging reporter gene expression with PET. Current methods for quantitating the images using the percentage injected dose per gram of tissue do not distinguish between the effects of probe transport and subsequent phosphorylation. We therefore investigated tracer kinetic models for 18F-FHBG dynamic microPET data and noninvasive methods for determining blood time-activity curves in an adenoviral gene delivery model in mice. METHODS: 18F-FHBG (approximately 7.4 MBq [approximately 200 microCi]) was injected into 4 mice; 18F-FHBG concentrations in plasma and whole blood were measured from mouse heart left ventricle (LV) direct sampling. Replication-incompetent adenovirus (0-2 x 10(9) plaque-forming units) with the E1 region deleted (n = 8) or replaced by HSV1-sr39tk (n = 18) was tail-vein injected into mice. Mice were dynamically scanned using microPET (approximately 7.4 MBq [approximately 200 microCi] 18F-FHBG) over 1 h; regions of interest were drawn on images of the heart and liver. Serial whole blood 18F-FHBG concentrations were measured in 6 of the mice by LV sampling, and 1 least-squares ratio of the heart image to the LV time-activity curve was calculated for all 6 mice. For 2 control mice and 9 mice expressing HSV1-sr39tk, heart image (input function) and liver image time-activity curves (tissue curves) were fit to 2- and 3-compartment models using Levenberg-Marquardt nonlinear regression. The models were compared using an F statistic. HSV1-sr39TK enzyme activity was determined from liver samples and compared with model parameter estimates. For another 3 control mice and 6 HSV1-sr39TK-positive mice, the model-predicted relative percentage of metabolites was compared with high-performance liquid chromatography analysis. RESULTS: The ratio of 18F-FHBG in plasma to whole blood was 0.84 +/- 0.05 (mean +/- SE) by 30 s after injection. The least-squares ratio of the heart image time-activity curve to the LV time-activity curve was 0.83 +/- 0.02, consistent with the recovery coefficient for the partial-volume effect (0.81) based on independent measures of heart geometry. A 3-compartment model best described 18F-FHBG kinetics in mice expressing HSV1-sr39tk in the liver; a 2-compartment model best described the kinetics in control mice. The 3-compartment model parameter, k3, correlated well with the HSV1-sr39TK enzyme activity (r2 = 0.88). CONCLUSION: 18F-FHBG equilibrates rapidly between plasma and whole blood in mice. Heart image time-activity curves corrected for partial-volume effects well approximate LV time-activity curves and can be used as input functions for 2- and 3-compartment models. The model parameter k3 from the 3-compartment model can be used as a noninvasive estimate for HSV1-sr39TK reporter protein activity and can predict the relative percentage of metabolites.     

Early rapid weight gain and current overweight in relation to asthma in adolescents born with very low birth weight

Early catch-up growth and subsequent overweight are suggested to be associated with later cardiovascular diseases and later type II diabetes. However, the impact of early catch-up growth and childhood overweight on the development of asthma has been less studied, particularly in children born with very low birth weight (VLBW). A birth cohort of 74 VLBW children (birth weight < or = 1500 g) was followed from birth and investigated on asthma at 12 yr of age. Early rapid weight gain was in one way defined as an increase of weight > or =1 standard deviation score (SDS) at 6 months of corrected postnatal age. Current overweight was defined by body mass index (BMI) exceeding 21.2 and 21.7 kg/m(2), respectively, for boys and girls at 12 yr of age. Current asthma was diagnosed by a pediatrician, according to asthma ever in combination with a positive response to hypertonic saline bronchial provocation test and/or wheeze at physical examination at 12 yr old. Being overweight at 12 yr of age was associated with an increased risk for current asthma in the VLBW children [crude odds ratio (OR): 5.5, 95% confidence interval (CI): 1.3-22.2]. After adjustment for early weight gain and neonatal risk, the OR of overweight increased nearly three times (adjusted OR: 15.3, 95% CI: 2.5-90.6). Early rapid weight gain seemed to be inversely associated with current asthma (adjusted OR: 0.49 for an increase of weight equal to 1 SDS, 95% CI: 0.23-1.02, p = 0.06). In addition, early rapid weight gain was inversely associated with the magnitude of bronchial responsiveness at 12 yr (coefficient -1.15, p < 0.01). There was a strong and positive association between overweight and asthma at 12 yr of age in the VLBW children. This strong association had been reduced by early rapid weight gain, possibly via the reduction of bronchial responsiveness.     

IFN-alpha-induced murine B16 melanoma cancer vaccine cells: induction and accumulation of cell-associated IL-15.

Long-term treatment of mouse cancer cells with interferon-alpha (IFN-alpha) converts parental B16 melanoma cells to B16alpha vaccine cells. Inoculation of syngeneic mice with B16alpha vaccine cells triggers immunity to the parental B16 tumor that is mediated by host macrophages, T cells, and natural killer (NK) cells. Lymph node cells from mice inoculated with irradiated B16alpha vaccine cells, but not with irradiated parental cells, proliferate when cultured in vitro, suggesting long-term in vivo activation of lymphoid cells. Long-term IFN-alpha treatment of B16alpha vaccine cells induced both interleukin-15 (IL-15) mRNA and IL-15 protein. The bulk of the induced IL-15 remained cell associated, either cytoplasmic or associated with the cell membrane. Immunofluorescence microscopy studies showed that the cell-associated IL-15 was broadly distributed throughout the cytoplasm. These observations suggest that long-term IFN-alpha treatment may induce primarily the truncated isoform of IL-15. Vaccination with irradiated B16alpha vaccine cells may promote tumor immunity by releasing high levels of cell-associated IL-15 when spontaneously lysed or directly killed by innate immune cells. The release of accumulated cell-associated IL-15 may then trigger a host T cell response to tumor antigens and cause host development of immunity to the B16 tumor cells.     

Mouse chromosome 9 quantitative trait loci for soft tissue regeneration: Congenic analysis and fine mapping

Development of gene therapies for wound healing will depend on the identification of the genes involved in wound healing and tissue regeneration. Previous quantitative trait loci (QTL) studies in mice using the ear punch model have shown that major QTL exist on chromosome (Chr) 9 for soft tissue regeneration. In this study, we have developed a congenic line that contains the Chr 9 QTL chromosomal region from super healer MRL/MpJ in the genomic background of poor-healing SJL/J. The phenotypic effect of this QTL was confirmed in male mice, where the congenic line has shown significant healing improvement over SJL. Fine mapping of the Chr 9 QTL region with 23 markers at an average distance of 4.2 Mb using a total of 1,564 MRL/MpJ x SJL/J F(2) mice revealed the presence of at least three QTL peaks, implying that three separate loci may contribute to the phenotypic effect of this QTL. Based on the 2-LOD intervals, the total QTL region was confined to a combined length of no more than 28.2 Mb. Application of a Bayesian shrinkage estimation indicated that a major locus was located in a region of just 1.3 Mb.