Kidney and Liver Injuries After Major Burns in Rats Are Prevented by Resolvin D2.

OBJECTIVES: Innate immune dysfunction after major burn injuries increases the susceptibility to organ failure. Lipid mediators of inflammation resolution, e.g., resolvin D2, have been shown recently to restore neutrophil functionality and reduce mortality rate in a rat model of major burn injury. However, the physiological mechanisms responsible for the benefic activity of resolvin D2 are not well understood. DESIGN: Prospective randomized animal investigation. SETTING: Academic research setting. SUBJECTS: Wistar male rats. INTERVENTIONS: Animals were subjected to a full-thickness burn of 30% total body surface area. Two hours after burn, 25 ng/kg resolvin D2 was administered IV and repeated every day, for 8 days. At day 10 post burn, 2 mg/kg of lipopolysaccharide was administered IV, and the presence of renal and hepatic injuries was evaluated at day 11 post burn by histology, immunohistochemistry, and relevant blood chemistry. MEASUREMENTS AND MAIN RESULTS: In untreated animals, we found significant tissue damage in the kidneys and liver, consistent with acute tubular necrosis and multifocal necrosis, and changes in blood chemistry, reflecting the deterioration of renal and hepatic functions. We detected less tissue damage and significantly lower values of blood urea nitrogen (26.4 ± 2.1 vs 36.0 ± 9.3 mg/dL; p ≤ 0.001), alanine aminotransferase (266.5 ± 295.2 vs 861.8 ± 813.7 U/L; p ≤ 0.01), and total bilirubin (0.13 ± 0.05 vs 0.30 ± 0.14 mg/dL; p ≤ 0.01) in resolvin D2-treated rats than in untreated animals. The mean blood pressure of all animals was above 65 mm Hg, indicating adequate tissue perfusion throughout the experiments. We measured significantly larger amounts of chromatin in the circulation of untreated than of resolvin D2-treated rats (575.1 ± 331.0 vs 264.1 ± 122.4 ng/mL; p ≤ 0.05) and identified neutrophil extracellular traps in kidney and liver tissues from untreated rats, consistent with the tissue damage. CONCLUSIONS: Pathologic changes in kidney and liver tissues in a rat model of major burn and endotoxin insults are ameliorated by resolvin D2.

Simvastatin reduces burn injury-induced splenic apoptosis via downregulation of the TNF-α/NF-κB pathway.

OBJECTIVE: Recent studies have suggested that epidermal burn injuries are associated with inflammation and immune dysfunction. Simvastatin has been shown to possess potent anti-inflammatory properties. Thus, we hypothesized that simvastatin protects against burn-induced apoptosis in the spleen via its anti-inflammatory activity. METHODS: Wild-type, tumor necrosis factor alpha knockout (TNF-α KO) and NF-κB KO mice were subjected to full-thickness burn injury or sham treatment. The mice then were treated with or without simvastatin, and the spleen was harvested to measure the extent of apoptosis. Expression levels of TNF-α and NF-κB were also determined in spleen tissue and serum. RESULTS: Burn injury induced significant splenic apoptosis and systemic cytokine production. Simvastatin protected the spleen from apoptosis, reduced cytokine production in the serum, and increased the survival rate. Simvastatin decreased burn-induced TNF-α and NF-κB expression in the spleen and serum. TNF-α and NF-κB KO mice demonstrated lower levels of apoptosis in spleen in response to burn injury. Simvastatin did not further decrease burn-caused apoptosis and mortality in either strain of KO mice. CONCLUSIONS: Simvastatin reduces burn-induced splenic apoptosis via downregulation of the TNF-α/NF-κB pathway.

Resolvin D2 restores neutrophil directionality and improves survival after burns.

Following severe burns and trauma injuries, the changes of neutrophil migratory phenotype are a double-edged sword. Activated neutrophils migrate into injured tissues and help contain microbial infections, but they can also enter normal tissues and damage vital organs. Depleting the neutrophils from circulation protects vital organs against neutrophil-induced damage but leaves the body exposed to infectious complications. Here we show that restoring normal neutrophil migratory phenotype in rats with burn injuries correlates with improved survival in a classical double-injury model of sequential burn and septic insults. We uncovered that the directionality of neutrophils from burned rats can be restored both in vitro by 1 nM resolvin D2 (RvD2) and in vivo by RvD2 for 7 d, 25 ng/kg body mass (8-10 ng/rat). Restoring neutrophil directionality dramatically increases survival after a second septic insult at d 9 postburn. Survival of RvD2-treated animals increases from 0 to 100% after lipopolysaccharide injection and is extended by 1 wk after cecal ligation. Survival does not significantly increase when the restoration of neutrophil directionality is incomplete, following shorter regimens of RvD2. We conclude that restoring neutrophil directionality using RvD2 could have prophylactic value and delay lethal complications after burn injuries.

Membrane potential-dependent uptake of 18F-triphenylphosphonium--a new voltage sensor as an imaging agent for detecting burn-induced apoptosis.

BACKGROUND: Mitochondrial dysfunction has been closely related to many pathologic processes, such as cellular apoptosis. Alterations in organelle membrane potential are associated with mitochondrial dysfunction. A fluorine-18 labeled phosphonium compound: (18)F-triphenylphosphonium ((18)F-TPP) was prepared to determine its potential use as a mitochondria-targeting radiopharmaceutical to evaluate cellular apoptosis. METHODS: Studies were conducted in both ex vivo cell lines and in vivo using a burned animal model. Uptake of (18)F-TPP was assessed in PC-3 cells by gamma counting under the following conditions: graded levels of extracellular potassium concentrations, incubation with carbonyl cyanide m-chlorophenylhydrazone and staurosporine. Apoptosis was studied in a burn animal model using terminal deoxynucleotidyl transferase dUTP nick end labeling staining and simultaneous assessment of (18)F-TPP uptake by biodistribution. RESULTS: We found that stepwise membrane depolarization by potassium (K) resulted in a linear decrease in (18)F-TPP uptake, with a slope of 0.62 ± 0.08 and a correlation coefficient of 0.936 ± 0.11. Gradually increased concentrations of m-chlorophenylhydrazone lead to decreased uptake of (18)F-TPP. Staurosporine significantly decreased the uptake of (18)F-TPP in PC-3 cells from 14.2 ± 3.8% to 5.6 ± 1.3% (P < 0.001). Burn-induced significant apoptosis (sham: 4.4 ± 1.8% versus burn: 24.6 ± 6.7 %; P < 0.005) and a reduced uptake of tracer in the spleens of burn-injured animals as compared with sham burn controls (burn: 1.13 ± 0.24% versus sham: 3.28 ± 0.67%; P < 0.005). Biodistribution studies demonstrated that burn-induced significant reduction in (18)F-TPP uptake in spleen, heart, lung, and liver, which were associated with significantly increased apoptosis. CONCLUSIONS: (18)F-TPP is a promising new voltage sensor for detecting mitochondrial dysfunction and apoptosis in various tissues.

Brown adipose tissue and its modulation by a mitochondria-targeted peptide in rat burn injury-induced hypermetabolism.

Hypermetabolism is a prominent feature of burn injury, and altered mitochondria function is presumed to contribute to this state. Recently, brown adipose tissue (BAT) was found to be present not only in rodents but also in humans, and its activity is associated with resting metabolic rate. In this report, we elucidate the relationship between burn injury-induced hypermetabolism and BAT activity and the possible role of the mitochondria-targeted peptide SS31 in attenuating burn injury-induced hypermetabolism by using a rat burn injury model. We demonstrate that burn injury induces morphological changes in interscapular BAT (iBAT). Burn injury was associated with iBAT activation, and this effect was positively correlated with increased energy expenditure. BAT activation was associated with augmentation of mitochondria biogenesis, and UCP1 expression in the isolated iBAT mitochondria. In addition, the mitochondria-targeted peptide SS31 attenuated burn injury-induced hypermetabolism, which was accompanied by suppression of UCP1 expression in isolated mitochondria. Our results suggest that BAT plays an important role in burn injury-induced hypermetabolism through its morphological changes and expression of UCP1.

Simvastatin protects hepatocytes from apoptosis by suppressing the TNF-α/caspase-3 signaling pathway in mice with burn injury.

OBJECTIVE: To investigate the liver cellular apoptosis in response to burn injury and find out if statin treatment can ameliorate this process. The hypothesis is that statin may modulate apoptosis-related gene expression and thereby reduce hepatocytic apoptosis after burn injury. METHODS: Mice were subjected to 30% full-thickness burn injury and then treated either with or without simvastatin. The livers were harvested for histological assessment and determinations of gene expression. To investigate the mechanism involved, tumor necrosis factor (TNF)-α and caspase-3 knockout (KO) mice were also used to evaluate the effects of burn injury and simvastatin treatment on burn-induced liver injury. The effects of simvastatin on TNF-α and caspase-3 expressions were also evaluated in cultured mouse hepatocytes. RESULTS: Burn injury induced significant liver damage, which was indicated by striking levels of apoptosis. Simvastatin reduced the apoptotic index in the livers of mice with burn injury and this effect could be abrogated by TNF-α or caspase-3 inhibitors. Simvastatin also decreased burn-induced TNF-α and caspase-3 expression in the liver. TNF-α and caspase-3 KO mice demonstrated lower levels of apoptotic hepatocytes in response to burn, and simvastatin did not further decrease hepatocyte apoptosis in either strain of KO mice. An in vitro study demonstrated that simvastatin suppresses TNF-α and caspase-3 expression in primary cultures of mouse hepatocytes. CONCLUSIONS: Simvastatin reduces mouse hepatocyte apoptosis by suppressing expression of the TNF-α/caspase-3 pathway.

Potential of 18F-FDG PET toward personalized radiotherapy or chemoradiotherapy in lung cancer.

PURPOSE: We investigated the metabolic response of lung cancer to radiotherapy or chemoradiotherapy by (18)F-FDG PET and its utility in guiding timely supplementary therapy. METHODS: Glucose metabolic rate (MRglc) was measured in primary lung cancers during the 3 weeks before, and 10-12 days (S2), 3 months (S3), 6 months (S4), and 12 months (S5) after radiotherapy or chemoradiotherapy. The association between the lowest residual MRglc representing the maximum metabolic response (MRglc-MMR) and tumor control probability (TCP) at 12 months was modeled using logistic regression. RESULTS: We accrued 106 patients, of whom 61 completed the serial (18)F-FDG PET scans. The median values of MRglc at S2, S3 and S4 determined using a simplified kinetic method (SKM) were, respectively, 0.05, 0.06 and 0.07 µmol/min/g for tumors with local control and 0.12, 0.16 and 0.19 µmol/min/g for tumors with local failure, and the maximum standard uptake values (SUVmax) were 1.16, 1.33 and 1.45 for tumors with local control and 2.74, 2.74 and 4.07 for tumors with local failure (p < 0.0001). MRglc-MMR was realized at S2 (MRglc-S2) and the values corresponding to TCP 95 %, 90 % and 50 % were 0.036, 0.050 and 0.134 µmol/min/g using the SKM and 0.70, 0.91 and 1.95 using SUVmax, respectively. Probability cut-off values were generated for a given level of MRglc-S2 based on its predicted TCP, sensitivity and specificity, and MRglc ≤0.071 µmol/min/g and SUVmax ≤1.45 were determined as the optimum cut-off values for predicted TCP 80 %, sensitivity 100 % and specificity 63 %. CONCLUSION: The cut-off values (MRglc ≤0.071 µmol/min/g using the SKM and SUVmax ≤1.45) need to be tested for their utility in identifying patients with a high risk of residual cancer after standard dose radiotherapy or chemoradiotherapy and in guiding a timely supplementary dose of radiation or other means of salvage therapy.

Glucose metabolism during the early "flow phase" after burn injury.

BACKGROUND: Burn injury (BI) is associated with insulin resistance (IR) and hyperglycemia which complicate clinical management. We investigated the impact of BI on glucose metabolism in a rabbit model of BI using a combination of positron emission tomography (PET) and stable isotope studies under euglycemic insulin clamp (EIC) conditions. MATERIALS AND METHODS: Twelve male rabbits were subjected to either full-thickness BI (B) or sham burn. An EIC condition was established by constant infusion of insulin, concomitantly with a variable rate of dextrose infusion 3 d after treatment. PET imaging of the hind limbs was conducted to determine the rates of peripheral O(2) and glucose utilization. Each animal also received a primed constant infusion of [6,6-(2)H(2)] glucose to determine endogenous glucose production. RESULTS: The fasting blood glucose in the burned rabbits was higher than that in the sham group. Under EIC conditions, the sham burn group required more exogenous dextrose than the B group to maintain blood glucose at physiological levels (22.2 ± 2.6 versus 13.3 ± 2.9 mg/min, P < 0.05), indicating a state of IR. PET imaging demonstrated that the rates of O(2) consumption and (18)F 2-fluoro-2-deoxy-D-glucose utilization by skeletal muscle remained at similar levels in both groups. Hepatic gluconeogenesis determined by the stable isotope tracer study was found significantly increased in the B group. CONCLUSIONS: These findings demonstrated that hyperglycemia and IR develop during the early "flow phase" after BI. Unsuppressed hepatic gluconeogenesis, but not peripheral skeletal muscular utilization of glucose, contributes to hyperglycemia at this stage.

5-HT2 receptor distribution shown by [18F] setoperone PET in high-functioning autistic adults.

The serotonergic system is implicated in disordered emotional behavior. Autism is characterized by impaired processing of emotional information. The serotonergic (5-HT) system is also critically involved in brain development, and abnormal brain synthesis of serotonin is observed in autism. Furthermore, whole blood and platelet serotonin have been reported to be elevated in autism. The authors examined the CNS serotonin system in autism in vivo. 5-HT2 receptors were visualized by PET imaging of [18F]setoperone-binding in this pilot study of 6 high-functioning autistic adults and 10 matched-control participants. Autism subjects had less thalamic [18F]setoperone binding than controls, when covaried for age, but no difference reached significance in other areas. A negative relationship between thalamic binding and history of language impairment was also observed. Further studies will be needed to gain a clearer picture of the role of the 5-HT system in autism.

Farnesyltransferase inhibitor FTI-277 reduces mortality of septic mice along with improved bacterial clearance.

Treatment with statins, inhibitors of HMG-CoA reductase, extends the survival of septic mice. However, the molecular mechanisms underlying the cholesterol-lowering, independent beneficial effects of statins in sepsis are poorly understood. The inhibition of protein isoprenylation, namely farnesylation and geranylgeranylation, has been proposed as a mediator of the pleiotropic protective effects of statins, although direct evidence is lacking. Major features of sepsis-induced immune suppression include T-cell dysfunction, which is characterized by apoptosis of splenic T cells, increased CD4(+)Foxp3(+) regulatory T cells (Tregs), and suppression of type 1 helper T-cell response [e.g., interferon-γ (IFN-γ) secretion] in mice. Here, we show that the induction of sepsis by cecal ligation and puncture (CLP) resulted in increases in farnesyltransferase activity and farnesylated proteins in the spleen relative to sham operation. Treatment with farnesyltransferase inhibitor N-[4-[2(R)-amino-3-mercaptopropyl]amino-2-phenylbenzoyl]methionine methyl ester trifluoroacetate salt (FTI-277) (25 mg/kg b.wt. i.p.) at 2 h after CLP blocked the increase in farnesylated proteins and improved survival and bacterial clearance of septic mice. FTI-277 reverted to or mitigated sepsis-induced apoptosis in spleen and thymus, increased splenic CD4(+)Foxp3(+) Tregs, and suppressed IFN-γ secretion and proliferation of splenocytes in response to anti-CD3+CD28 antibodies in mice. Moreover, FTI-277 promoted macrophage phagocytotic activity in septic mice. These results indicate that elevation in protein farnesylation plays a role in derangements in immune function and mortality of septic mice. These findings suggest that prevention of immune dysfunction might contribute to FTI-277-induced improvement in survival of septic mice. These data highlight protein farnesyltransferase as a novel potential molecular target to reduce the mortality of patients with sepsis.

Iodine-124 as a label for pharmacological PET imaging.

With the growing number of biotechnology products and drug delivery systems entering preclinical and clinical studies, pharmacological imaging studies with PET play an increasingly significant role. Such studies often require investigation of slow and complex pharmacokinetics (PK). This suggests labeling of the drug candidate with radionuclides that have long physical half-lives. Among the currently available PET positron emitters, ¹²4I has the longest physical half-life (4.2 days). This, combined with the well-investigated behavior of iodine in vivo, makes ¹²4I very attractive for pharmacological studies. However, the high energy of the positrons emitted by ¹²4I and the presence of single photons in the ¹²4I emission can potentially introduce limitations in the quantitative analysis of the images. The objective of this research was to determine whether the use of ¹²4I as a PET label provides data quality suitable for PK studies. The study was carried out using MicroPET P4 scanner (Siemens/Concorde Microsystems). Spatial resolution, count-rate performance, sensitivity and scatter fraction were measured using a line source and a cylindrical phantom. Model animal studies in rats and cynomolgus monkeys were carried out using human recombinant proteins. The proteins were labeled with ¹²4I, up to 185 MBq/mg. The transaxial and axial spatial resolutions in the center of the camera were satisfactory and higher for OSEM3D/MAP than FORE-2DFBP (FWHM 2.52 vs 3.31 mm, and 3.10 vs 3.69 mm). Linearity of the true coincidence count-rate was observed up to 44 MBq. Animal studies demonstrated excellent delineation and resolution of even very small organs. At optimal doses, 2-10 MBq per animal for rodents and 4-10 MBq per kg of body weight for larger animals, the quality of numerical data was appropriate for PK analysis in all experimental timeframes from minutes (dynamic studies) to 10 days. Overall, the data suggest that ¹²4I is an excellent label for quantitative pharmacological PET imaging studies.

Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer.

The effects of vascular endothelial growth factor (VEGF) blockade on the vascular biology of human tumors are not known. Here we show here that a single infusion of the VEGF-specific antibody bevacizumab decreases tumor perfusion, vascular volume, microvascular density, interstitial fluid pressure and the number of viable, circulating endothelial and progenitor cells, and increases the fraction of vessels with pericyte coverage in rectal carcinoma patients. These data indicate that VEGF blockade has a direct and rapid antivascular effect in human tumors.

Self-organized patchiness in asthma as a prelude to catastrophic shifts.

Asthma is a common disease affecting an increasing number of children throughout the world. In asthma, pulmonary airways narrow in response to contraction of surrounding smooth muscle. The precise nature of functional changes during an acute asthma attack is unclear. The tree structure of the pulmonary airways has been linked to complex behaviour in sudden airway narrowing and avalanche-like reopening. Here we present experimental evidence that bronchoconstriction leads to patchiness in lung ventilation, as well as a computational model that provides interpretation of the experimental data. Using positron emission tomography, we observe that bronchoconstricted asthmatics develop regions of poorly ventilated lung. Using the computational model we show that, even for uniform smooth muscle activation of a symmetric bronchial tree, the presence of minimal heterogeneity breaks the symmetry and leads to large clusters of poorly ventilated lung units. These clusters are generated by interaction of short- and long-range feedback mechanisms, which lead to catastrophic shifts similar to those linked to self-organized patchiness in nature. This work might have implications for the treatment of asthma, and might provide a model for studying diseases of other distributed organs.

Evaluation of the effects of oral water and low-density barium sulphate suspension on bowel appearance on FDG-PET/CT.

The purpose of this study is to assess which of five bowel preparation regimes offers superior bowel distension and to assess if these regimes adversely affect FDG activity on PET/CT imaging. The study conformed to HIPAA regulations. Ninety patients were divided into five groups of 18 who received no oral contrast agent (group A); 900 ml of water orally (group B); or 900, 1,350, or 1,800 ml of LDB (groups C, D, E, respectively). PET/CT examinations were assessed quantitatively (bowel diameter, SUV) and qualitatively (visual assessment grading scale) for bowel distension and FDG activity by two blinded readers. ANOVA was utilized to determine if a statistically significant difference (SSD) existed between the groups in terms of distension and FDG uptake. Qualitatively superior bowel distension was observed in group C (LDB) compared to B (water) and greater distension was noted with increased volumes of LDB in C, D, and E. Quantitatively there was an SSD in mean distension between groups C and B (P < 0.001 except duodenum). Qualitatively and quantitatively there was no significant difference in bowel FDG uptake among the groups (P > 0.05). LDB as an oral contrast agent provides superior bowel distension over water and does not induce increased FDG bowel activity.

Dopamine release during human emotional processing.

Involvement of dopamine neurotransmission in human emotional processing is unclear but animal studies have indicated that it is critical for processing of fear response. In this experiment we examined dopaminergic involvement in the processing of human emotions. We used a novel dynamic molecular imaging technique to detect and map dopamine released during presentation of emotional stimuli. The technique exploited the competition between endogenously released dopamine and its ligand for receptor occupancy and involved dynamic voxel-wise measurement of the rate at which a dopamine receptor ligand ((18)F-Fallypride) was displaced from receptor sites during emotional processing. An increase in the rate indicated dopamine release. We found that the rate of ligand displacement increased significantly in the left amygdala, left medial temporal lobe (MTL) and left inferior frontal gyrus. The results provide the first direct evidence of dopaminergic modulation of human emotional processing and suggest that the modulation occurs at multiple levels of processing. This finding indicates that the neurocognitive models of human emotion should take into account dopaminergic effects, and that, there is a need to investigate whether manipulation of the dopaminergic system could be an alternate strategy for treatment of conditions in which emotional processing is impaired.

Metabolic tumor width parameters as determined on PET/CT predict disease-free survival and treatment response in squamous cell carcinoma of the esophagus.

MATERIALS AND METHODS: We investigated the utility of metabolic tumor width parameters in predicting response to chemoradiotherapy and in predicting disease-free survival in patients with esophageal cancer. Furthermore, we evaluated the possible confounding effect of therapy-induced esophagitis on the evaluation of treatment response. Forty-nine patients with squamous cell carcinoma, who had undergone positron emission tomography/computed tomography (PET/CT) exams before and after neoadjuvant chemoradiotherapy, were included in the study. In the slice with the maximum 2-deoxy-2-[F-18]fluoro-D: -glucose (FDG) uptake of the tumor, the following metabolic tumor width parameters were measured: Area of the tumor, maximum diameter of the tumor, maximum and mean standardized uptake value (SUV). Furthermore, the "diameter-SUV index" was calculated by multiplying the tumor diameter by the mean SUV. RESULTS: The decrease of the metabolic tumor diameter between pre- and post-treatment PET/CT scans was the single best predictor of treatment response and tumor-free survival. However, the accuracy of predicting response and survival was even higher when using the decrease of the "diameter-SUV index" as the metabolic criterion for treatment response. A decrease by more than 55% of the diameter-SUV index identified pathologic responders (n = 22) with a sensitivity of 91% and a specificity of 93%. Radiation esophagitis was found to have a significant impact on the assessment of treatment response when evaluating therapy response based on the maximum SUV, whereas no confounding effect of radiation esophagitis was seen when evaluating therapy response based on the tumor diameter or the diameter-SUV index. CONCLUSION: The present study shows that tumor width parameters, especially the tumor diameter or the combination of diameter and SUV in the "diameter-SUV index", are valuable for predicting tumor-free survival and treatment response independent from the presence of radiation esophagitis.

Amyloid deposition begins in the striatum of presenilin-1 mutation carriers from two unrelated pedigrees.

The amyloid cascade hypothesis suggests that the aggregation and deposition of amyloid-beta protein is an initiating event in Alzheimer's disease (AD). Using amyloid imaging technology, such as the positron emission tomography (PET) agent Pittsburgh compound-B (PiB), it is possible to explore the natural history of preclinical amyloid deposition in people at high risk for AD. With this goal in mind, asymptomatic (n = 5) and symptomatic (n = 5) carriers of presenilin-1 (PS1) mutations (C410Y or A426P) that lead to early-onset AD and noncarrier controls from both kindreds (n = 2) were studied with PiB-PET imaging and compared with sporadic AD subjects (n = 12) and controls from the general population (n = 18). We found intense and focal PiB retention in the striatum of all 10 PS1 mutation carriers studied (ages 35-49 years). In most PS1 mutation carriers, there also were increases in PiB retention compared with controls in cortical brain areas, but these increases were not as great as those observed in sporadic AD subjects. The two PS1 mutation carriers with a clinical diagnosis of early-onset AD did not show the typical regional pattern of PiB retention observed in sporadic AD. Postmortem evaluation of tissue from two parents of PS1C410Y subjects in this study confirmed extensive striatal amyloid deposition, along with typical cortical deposition. The early, focal striatal amyloid deposition observed in these PS1 mutation carriers is often is not associated with clinical symptoms.

[18F]2-fluoro-2-deoxy-D-glucose positron emission tomography demonstration of estrogen negative and positive feedback on luteinizing hormone secretion in women.

CONTEXT: Precise regulation of the neuroendocrine components of the female reproductive axis involves both negative and positive feedback of estrogen on gonadotropin secretion. OBJECTIVE: Our objective was to determine the hypothalamic and/or pituitary sites of estrogen negative and positive feedback using neuroimaging techniques. DESIGN AND SETTING: A graded estrogen infusion protocol was administered at a General Clinical Research Center in an academic medical center. SUBJECTS: Healthy postmenopausal women (n = 11) were recruited for study. INTERVENTIONS: Serum samples were measured every 4 h. A structural magnetic resonance imaging was performed at baseline, and [(18)F]2-fluoro-2-deoxy-d-glucose ((18)FDG) positron emission tomography was performed at baseline and 24 and 72 h. FDG positron emission tomography was co-registered with magnetic resonance imaging scans, and region of interest analysis was performed. MAIN OUTCOME MEASURES: Serum LH and estradiol were assessed. Normalized values for glucose uptake were extracted from each region of interest for each subject at each time point. RESULTS: A decrease in normalized (18)FDG uptake was apparent in the hypothalamus at 24 h (P < 0.02) associated with decreased LH (P < 0.0005). The increase in LH at 72 h (P < 0.0005) was associated with increased pituitary (18)FDG uptake (P < 0.02) but no change in hypothalamic uptake. CONCLUSIONS: Changes in (18)FDG uptake as a measure of metabolic activity can be demonstrated in the hypothalamus and pituitary in association with discrete hormonal events. Results are consistent with mediation of estrogen negative feedback on LH at the hypothalamus, whereas estrogen positive feedback occurs at the pituitary with no evidence of increased hypothalamic activity in women.

Adenocarcinomas of the esophagus: response to chemoradiotherapy is associated with decrease of metabolic tumor volume as measured on PET-CT. Comparison to histopathologic and clinical response evaluation.

PURPOSE: We determined whether evaluation of treatment response is feasible by measuring metabolic tumor volume parameters on 18F-FDG (Fluorodeoxyglucose) PET-CT (Positron emission tomography-Computed tomography). We compared the response evaluation based on metabolic tumor volume parameters to a histopathologic and clinical response evaluation (clinical response criteria: RECIST criteria=Response evaluation criteria in solid tumors, and WHO criteria=World health organization). PATIENTS AND METHODS: A total of 51 study subjects with adenocarcinomas (Type I due to Siewert classification) of the esophagus underwent PET-CT scans before and after neoadjuvant chemoradiotherapy. Tumor volume, maximum and mean standardized uptake values (SUV) were assessed before and after chemoradiotherapy. Furthermore, the total lesion glycolysis (TLG) was calculated by multiplying the tumor volume by the mean SUV of the volume. Clinical response evaluation was performed with endoscopic ultrasound and CT using RECIST and WHO criteria. The reference standard for treatment response was the postsurgical histopathology. RESULTS: The decrease of tumor volume between the pre- and post-treatment PET-CT scans was a better predictor of histopathologic response and survival than the decrease of the SUV and of the clinical response evaluation based on RECIST and WHO criteria. The highest accuracy, however, was achieved when using the TLG for the identification of treatment responders. A decrease of the TLG by > 78% between pre- and post-therapy scans predicted histopathologic response with a sensitivity and specificity of 91% and 93%, respectively. CONCLUSIONS: Tumor volume and TLG can be used to assess treatment response and survival in patients with esophageal adenocarcinoma.

Evaluation of prefrontal-hippocampal effective connectivity following 24 hours of estrogen infusion: an FDG-PET study.

Although several functional neuroimaging studies have addressed the relevance of hormones to cerebral function, none have evaluated the effects of hormones on network effective connectivity. Since estrogen enhances synaptic connectivity and has been shown to drive activity across neural systems, and because the hippocampus and prefrontal cortex (PFC) are putative targets for the effects of estrogen, we hypothesized that effective connectivity between these regions would be enhanced by an estrogen challenge. In order to test this hypothesis, FDG-PET scans were collected in eleven postmenopausal women at baseline and 24h after a graded estrogen infusion. Subtraction analysis (SA) was conducted to identify sites of increased cerebral glucose uptake (CMRglc) during estrogen infusion. The lateral PFC and hippocampus were a priori sites for activation; SA identified the right superior frontal gyrus (RSFG; MNI coordinates 18, 60, 28) (SPM2, Wellcome Dept. of Cognitive Neurology, London, UK) as a site of increased CMRglc during estrogen infusion relative to baseline. Omnibus covariate analysis conducted relative to the RSFG identified the right hippocampus (MNI coordinates: 32, -32, -6) and right middle frontal gyrus (RMFG; MNI coordinates: 40, 22, 52) as sites of covariance. Path analysis (Amos 5.0 software) revealed that the path coefficient for the RSFG to RHIP path differed from zero only during E2 infusion (p<0.05); moreover, the magnitude of the path coefficient for the RHIP to RMFG path showed a significant further increase during the estrogen infusion condition relative to baseline [Deltachi(2)=4.05, Deltad.f.=1, p=0.044]. These findings are consistent with E2 imparting a stimulatory effect on effective connectivity within prefrontal-hippocampal circuitry. This holds mechanistic significance for resting state network interactions and may hold implications for mood and cognition.