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In humans, failure to express the fragile X mental retardation protein (FMRP) gives rise to fragile X syndrome, the most common form of inherited mental retardation. A fragile X knockout (fmr1 KO) mouse has been described that has some of the characteristics of patients with fragile X syndrome, including immature dendritic spines and subtle behavioral deficits. In our behavioral studies, fmr1 KO mice exhibited hyperactivity and a higher rate of entrance into the center of an open field compared with controls, suggesting decreased levels of anxiety. Our finding of impaired performance of fmr1 KO mice on a passive avoidance task is suggestive of a deficit in learning and memory. In an effort to understand what brain regions are involved in the behavioral abnormalities, we applied the [ 14 C]deoxyglucose method for the determination of cerebral metabolic rates for glucose (CMR glc). We measured CMRglc in 38 regions in adult male fmr1 KO and WT littermates. We found CMR glc was higher in all 38 regions in fmr1 KO mice, and in 26 of the regions, differences were statistically significant. Differences in CMR glc ranged from 12% to 46%, and the greatest differences occurred in regions of the limbic system and primary sensory and posterior parietal cortical areas. Regions most affected are consistent with behavioral deficiencies and regions in which FMRP expression is highest. Higher CMR glc in fragile X mice may be a function of abnormalities found in dendritic spines.

Two strains of Raoultella planticola and one of Raoultella ornithinolytica showing carbapenem resistance were recovered from patients hospitalized in New Jersey and Ohio. All patients had received previous antimicrobial treatment, including carbapenems. These strains harbored bla KPC-2 and bla KPC-3 . Carbapenemase genes were embedded in isoforms of Tn4401 and were plasmidic and chromosomal in location.Raoultella species are gram-negative aerobic bacilli belonging to the Enterobacteriaceae family that are closely related to Klebsiella spp. (7). These environmental organisms, infrequently causing human infections, appear to have pathogenicity similar to that of Klebsiella pneumoniae (8). The first human Raoultella spp. invasive infection was described in 1984, and bloodstream infections have been reported, though rarely (1). Studies have shown that 0.2 to 19.0% of isolates initially identified as Klebsiella spp. were Raoultella spp. by 16S rRNA analysis and that the prevalence of these organisms in clinical settings can vary geographically (8).(This work was presented at the 19th European Conference of Clinical Microbiology and Infectious Diseases, Helsinki, Finland, 2009.) A total of 7,248 Enterobacteriaceae isolates collected in medical centers from North America, Latin America, and Europe during 2008 were susceptibility tested by the reference broth microdilution method and interpretation criteria (3, 4). Isolates displaying imipenem and/or meropenem MICs of Ն2 g/ml were tested with the modified Hodge test (MHT) using imipenem and meropenem disks (4) and multiplex PCRs for the detection of carbapenemase-encoding genes, including bla IMP , bla VIM , bla KPC, bla SME , and bla GES variants and bla IMI , bla NMC-A , and bla .Among 134 (1.8% overall) isolates that were nonsusceptible to carbapenems, three (2.2%) Raoultella isolates from bloodstream infections were observed. MHT was positive for all three strains, and PCRs were positive for bla KPC . Sequencing of 16S rRNA revealed that two isolates were R. planticola (from Ohio and New Jersey) and one was R. ornithinolytica (from New Jersey). The isolates from New Jersey were detected in the same hospital and harbored bla , whereas the strain from Ohio carried bla KPC-2 . The clinical histories of the patients presenting infections with KPC-producing Raoultella spp. are summarized below. Case 1. An 83-year-old female patient was admitted to a hospital (Ohio) with a diagnosis of community-acquired bacterial pneumonia in May 2008. Sputum, paracentesis, and blood cultures were negative. Urine culture grew Escherichia coli, and the patient received courses of moxifloxacin, ceftriaxone, azithromycin, and meropenem. The patient was discharged and returned after 3 weeks with respiratory complaints. A tracheal-aspirate specimen grew a multidrug-resistant A. baumannii strain, and blood culture grew an enteric-like gram-negative bacillus (R. planticola). The patient subsequently died.Case 2. The patient was a 64-year-old man admitted to a hospital (New Jersey) in Septe...

The confounding effect of recycling of amino acids derived from tissue protein breakdown into the precursor pool for protein synthesis has been an obstacle to adapting in vivo methods for determination of regional rates of cerebral protein synthesis (rCPS) to positron emission tomography (PET). We used a kinetic modeling approach to estimate lambda, the fraction of the precursor pool for protein synthesis derived from arterial plasma, and to measure rCPS in three anesthetized adult monkeys dynamically scanned after a bolus injection of L-[1-11C]leucine. In the same animals, lambda was directly measured in a steady-state terminal experiment, and values showed excellent agreement with those estimated in the PET studies. In three additional monkeys rCPS was determined with the quantitative autoradiographic L-[1-14C]leucine method. In whole brain and cerebellum, rates of protein synthesis determined with the autoradiographic method were in excellent agreement with those determined with PET, and regional values were in good agreement when differences in spatial resolution of the two methods were taken into account. Low intrasubject variability was found on repeated PET studies. Our results in anesthetized monkey indicate that, by using a kinetic modeling approach to correct for recycling of tissue amino acids, quantitatively accurate and reproducible measurement of rCPS is possible with L-[1-11C]leucine and PET.

Measurements of regional rates of cerebral protein synthesis (rCPS) require correction for the effect of recycling of tissue amino acids back into the precursor pool for protein synthesis. The fraction of the precursor pool derived from arterial plasma, lambda, can be evaluated as the steady-state ratio of the specific activity of leucine in the tissue tRNA-bound fraction to that in arterial plasma. While lambda can be directly measured in terminal experiments in animals, an alternative method is required for use with PET. We report a method to estimate lambda based on a kinetic model of labeled and unlabeled leucine and labeled CO2 in the tissue. The kinetic model is also used to estimate the amount of labeled protein and rCPS. We measured time courses of [14C]leucine, [14C]protein, and 14CO2 in the blood and brain of anesthetized rats and estimated parameters of the kinetic model from these data. Simulation studies based on the kinetic parameters were then performed to examine the feasibility of this approach for use with L-[1-11C]leucine and PET. Lambda and rCPS were estimated with low bias, which suggests that PET can be used for quantitative measurement of rCPS with L-[1-11C]leucine and a kinetic modeling approach for correction for recycling of tissue amino acids.

Background Teprotumumab, a novel IGF-1R antibody was recently shown to significantly reduce the signs of active Thyroid eye disease (TED). The current study reviews its efficacy in chronic TED. Methods In this retrospective review, consecutive patients with chronic stable TED (>2 years), who had received ≥3 infusions of teprotumumab were included. All patients had measurements of proptosis, and calculation of the CAS and diplopia scores before and after therapy. Five-point strabismus scores were also calculated. Patients who had imaging within 4 months prior to therapy and 6 weeks post therapy underwent orbital 3D volumetric analysis. Results Thirty-one patients met the inclusion criteria. The mean (SD) duration of TED was 81 months (56) and the mean (SD) number of infusions received by each patient was 7 (2). Mean (SD) reduction in proptosis for each study orbit was 3.5 mm (0.4) and 3 mm (0.3) for the fellow orbit. The CAS response was 90% for the study orbit and 87% for the fellow orbit. Of the 15 patients who had diplopia at baseline, 67% had a clinically significant response, while 47% had complete resolution following treatment. Following teprotumumab, mean (SD) reduction of muscle tissue was 2011 mm3 (1847) in the study orbit and 1620 mm3 (1759) in the fellow orbit. The mean (SD) reduction of fat volume was 2101 mm3 (1681) in the study orbit and 1370 mm3 (1181) in the fellow orbit. Conclusion Teprotumumab significantly reduces proptosis, inflammation, diplopia, strabismus and orbital soft tissue volume in patients with chronic TED.

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