Haemaphysalis longicornis tick bites are a possible cause of red meat allergy in Japan.

Recent studies revealed that Amblyomma or Ixodes tick bites may cause red meat allergy, in which galactose-α-1,3-galactose (α-Gal) is a major IgE-binding epitope. The incidence of red meat allergy is high in Shimane Prefecture, as is tick-transmitted Japanese spotted fever. Therefore, we speculated that tick bites may cause these meat allergies. The carbohydrate α-Gal was detected in the salivary gland protein of Haemaphysalis longicornis (H. longicornis), the vector for Japanese spotted fever, by immunoblotting using anti-α-Gal antibody. H. longicornis salivary gland protein-specific IgE was detected in the sera of 24 of 30 patients with red meat allergies. Sensitization to tick salivary gland protein containing α-Gal is possibly a major etiology of red meat allergy; the carbohydrate plays a crucial role in its allergenicity. These results further indicate that the α-Gal epitope is present not only in Amblyomma or Ixodes, but also in Haemaphysalis.

Relative incidences and outcomes of Clostridium difficile infection following transplantation of unrelated cord blood, unrelated bone marrow, and related peripheral blood in adult patients: a single institute study.

BACKGROUND: Clostridium difficile is a major cause of nosocomial diarrhea. The incidence and prognosis of C. difficile-associated diarrhea (CDAD) has not yet been assessed in adult patients after unrelated cord blood transplantation (uCBT). METHODS: The medical records of 135 adult unrelated cord blood transplant recipients were reviewed retrospectively to investigate the clinical features of CDAD after uCBT. These data were compared to medical records of 39 unrelated bone marrow transplant recipients and 27 related peripheral blood stem cell transplant recipients as controls. RESULTS: A total of 17 recipients developed CDAD, with onset occurring at a median of 22 days (range, 0-56 days) after transplantation. Among the unrelated cord blood transplant recipients, 11 (9%) developed CDAD. These results were comparable with those of CDAD after unrelated bone marrow transplantation (uBMT) (2/39, 6%) and related peripheral blood stem cell transplantation (rPBSCT) (4/27, 16%) (P=0.37). Fifteen of the infected recipients were successfully treated with oral metronidazole, vancomycin, or cessation of antibiotics. The remaining 2 recipients who developed CDAD after uCBT died of other causes. The development of CDAD did not negatively affect overall survival after uCBT. CONCLUSIONS: These data indicate that the incidence and prognosis of CDAD after uCBT are comparable with those after uBMT and rPBSCT.

Rapidly progressive fatal hemorrhagic pneumonia caused by Stenotrophomonas maltophilia in hematologic malignancy.

BACKGROUND: Pneumonia caused by Stenotrophomonas maltophilia is rare, but can be lethal in severely immunocompromised patients. However, its clinical course remains unclear. PATIENTS AND METHODS: Patients with pneumonia caused by S. maltophilia in Toranomon Hospital (890 beds, Tokyo, Japan) were reviewed retrospectively between April 2006 and March 2010. RESULTS: During the study period, 10 cases of S. maltophilia pneumonia were identified. Seven patients had acute myeloid leukemia, 2 had myelodysplastic syndrome, and 1 had malignant lymphoma. All patients developed symptoms after allogeneic hematopoietic stem cell transplantation (HSCT). Five patients received first cord blood transplantation (CBT), 4 patients received second CBT, and 1 patient received first peripheral blood stem cell transplantation (PBSCT). The overall incidence of S. maltophilia pneumonia among 508 patients who received HSCT during the period was 2.0%. The incidence was 0% (0/95) in patients after bone marrow transplantation, 0.8% (1/133) after PBSCT, and 3.2% (9/279) after CBT. Pneumonia developed a median of 13.5 days (range, 6-40) after transplantation. At onset, the median white blood cell count was 10/µL (range, 10-1900), and the median neutrophil count was 0/µL (range, 0-1720). In all patients, S. maltophilia bacteremia developed with bloody sputum or hemoptysis. The 28-day mortality rate was 100%; the median survival after onset of pneumonia was 2 days (range, 1-10). CONCLUSIONS: Hemorrhagic S. maltophilia pneumonia rapidly progresses and is fatal in patients with hematologic malignancy. Attention should be particularly paid to the neutropenic phase early after HSCT or prolonged neutropenia due to engraftment failure. A prompt trimethoprim-sulfamethoxazole-based multidrug combination regimen should be considered to rescue suspected cases of S. maltophilia pneumonia in these severely immunosuppressed patients.

Cerebrospinal fluid metabolite and nigrostriatal dopaminergic function in Parkinson's disease.

OBJECTIVES: To evaluate the association between cerebrospinal fluid (CSF) homovanillic acid (HVA) concentrations and nigrostriatal dopaminergic function assessed by positron emission tomography (PET) imaging with carbon-11-labeled 2beta-carbomethoxy-3beta-(4-fluorophenyl)-tropane ((11)C-CFT), which can measure the dopamine transporter (DAT) density, in Parkinson's disease (PD). METHODS: (11)C-CFT PET scans and CSF examinations were performed on 21 patients with PD, and six patients with non-parkinsonian syndromes (NPS) as a control group. RESULTS: In the PD group, CSF HVA concentrations were significantly correlated with the striatal uptake of (11)C-CFT (r = 0.76, P < 0.01). However, in the NPS group, two indices were within the normal range. CONCLUSIONS: In PD, CSF HVA concentrations correlate with nigrostriatal dopaminergic function. Therefore, CSF HVA concentrations may be an additional surrogate marker for estimating the remaining nigrostriatal dopaminergic function in case that DAT imaging is unavailable.

Decreased dopamine D receptor binding in essential blepharospasm.

OBJECTIVES: The purpose of this study was to investigate whether dopamine D(2) receptor binding was altered in the striatum of essential blepharospasm patients. METHODS: Striatal dopamine D(2) receptor binding was measured with positron emission tomography and [(11)C]raclopride. We studied eight drug-naive patients with bilateral blepharospasm and eight age-matched normal controls. RESULTS: The uptake indices in the blepharospasm group were significantly reduced by 11.7% in the caudate (P < 0.005), 11.6% in the anterior putamen (P < 0.0001), and 10.3% in the posterior putamen (P < 0.005) relative to the control group. CONCLUSIONS: This study indicates decreased dopamine D(2) receptor binding in the entire striatal region of blepharospasm patients. The findings suggest that decreased dopamine D(2) receptor binding might be one of the predisposing factors that leads to the dysfunction of the motor circuit, resulting in the loss of broad inhibition of unwanted movements during an intended movement in blepharospasm patients.

Comparison of regional lower limb glucose metabolism in older adults during walking.

Glucose metabolism in lower limb muscles during walking has an important role in gait efficiency and endurance. The purpose of this study was to identify differences in muscle activity during walking between healthy young and older adults using positron emission tomography (PET) and [(18)F]fluorodeoxyglucose (FDG). Ten healthy young men (24 +/- 2 years) and 10 healthy older men (76 +/- 2 years) participated in this study. An FDG PET assessment of each subject was conducted after 50 min of treadmill walking. The images of glucose metabolism in 18 regions of interest were estimated from the standardized uptake value (SUV). The older adults showed a significantly higher FDG uptake in the semitendinosus, biceps femoris, iliacus, gluteus minimus, gluteus medius, and gluteus maximus muscles than the young adults: FDG uptake ratios of SUV in the old to SUV in the young were 3.02, 3.19, 1.66, 1.64, 3.68, and 3.05, respectively. During walking, the FDG uptake in older adults was higher in hamstrings and deep layer hip muscles than that in young adults. These results suggest that intervention to facilitate efficient muscle activity during walking should be practiced to improve gait endurance in older adults with impaired walking patterns.

Effects of an automated stride assistance system on walking parameters and muscular glucose metabolism in elderly adults.

OBJECTIVE: To identify the effects of an automated stride assistance system (SAS) on walking scores and muscle activities in the lower extremities of elderly people. METHODS: Seven healthy elderly men (73-81 years) participated in this study. Subjects walked continuously at a constant speed for 50 min on a treadmill with and without the SAS, which is a device to control the walk ratio (step length/cadence) and to add support power to the thigh during walking. A step counter equipped with an infrared device was used to record walking data. The average speeds during treadmill walking were 2.89-3.82 km/h without the SAS and 3.03-4.03 km/h with the SAS. Positron emission tomography (PET) and [18F]fluorodeoxyglucose (FDG) evaluation of glucose metabolism were conducted on each subject twice after walking with and without the SAS. RESULTS: Walk ratio, walking speed and step length were significantly improved in all subjects by the SAS, while cadence was significantly decreased by the SAS in all subjects except one. The SAS did not have a significant effect on glucose metabolism of the muscles of the lower extremities. There were no significant correlations between change in walking speed and change in glucose metabolism in each muscle without the SAS and with the SAS. In contrast, significant correlations between walking speed and glucose metabolism were shown in gluteus minimus (r = -0.929), hip-related muscles (r = -0.862), soleus (r = -0.907), and medial gastrocnemius (r = -0.952) without the SAS. With the SAS, there were significant correlations in gluteus medius (r = -0.899), hip-related muscles (r = -0.819), and medial gastrocnemius (r = -0.817) in the elderly subjects. CONCLUSIONS: The SAS increases walking scores in elderly people without increasing energy consumption of lower-extremity muscles. The elderly subjects with low walking speed showed higher glucose metabolism in hip-related muscles and triceps surae. Thus, this association suggested that decreased walking speed in elderly adults has a higher metabolic cost in these muscle regions.

Noninvasive Evaluation of CBF and Perfusion Delay of Moyamoya Disease Using Arterial Spin-Labeling MRI with Multiple Postlabeling Delays: Comparison with 15O-Gas PET and DSC-MRI.

BACKGROUND AND PURPOSE: Arterial spin-labeling MR imaging with multiple postlabeling delays has a potential to evaluate various hemodynamic parameters. To clarify whether arterial spin-labeling MR imaging can identify CBF and perfusion delay in patients with Moyamoya disease, we compared arterial spin-labeling, DSC, and 15O-gas PET in terms of their ability to identify these parameters. MATERIALS AND METHODS: Eighteen patients with Moyamoya disease (5 men, 13 women; ages, 21-55 years) were retrospectively analyzed. CBF values of pulsed continuous arterial spin-labeling using 2 postlabeling delays (short arterial spin-labeling, 1525 ms; delayed arterial spin-labeling, 2525 ms) were compared with CBF values measured by 15O-gas PET. All plots were divided into 2 groups by the cutoff of time-based parameters (the time of the maximum observed concentration, TTP, MTT, delay of MTT to cerebellum, and disease severity [symptomatic or not]). The ratio of 2 arterial spin-labeling CBFs (delayed arterial spin-labeling CBF to short arterial spin-labeling CBF) was compared with time-based parameters: time of the maximum observed concentration, TTP, and MTT. RESULTS: The short arterial spin-labeling-CBF values were significantly correlated with the PET-CBF values (r = 0.63; P = .01). However, the short arterial spin-labeling-CBF value dropped in the regions with severe perfusion delay. The delayed arterial spin-labeling CBF overestimated PET-CBF regardless of the degree of perfusion delay. Delayed arterial spin-labeling CBF/short arterial spin-labeling CBF was well correlated with the time of the maximum observed concentration, TTP, and MTT (ρ = 0.71, 0.64, and 0.47, respectively). CONCLUSIONS: Arterial spin-labeling using 2 postlabeling delays may detect PET-measured true CBF and perfusion delay in patients with Moyamoya disease. Provided its theoretic basis and limitations are considered, noninvasive arterial spin-labeling could be a useful alternative for evaluating the hemodynamics of Moyamoya disease.

Actions of human DNA glycosylases on uracil-containing DNA, methylated DNA and their reconstituted chromatins.

Extracts of human lymphoblastoid cells catalyzed complete release of uracil (Ura) from PBS1 DNA, which contains Ura instead of thymine as a normal component (Ura-DNA), and 3-methyladenine (3-MeAde) from DNA methylated with methyl methanesulfonate (Me-DNA). These two activities, Ura-DNA glycosylase and 3-MeAde-DNA glycosylase, differed in heat stability. Cell extracts released Ura more rapidly and 3-MeAde more slowly from alkali-denatured preparations of Ura- and Me-DNA, respectively, than from native DNA's. On incubation with reconstituted chromatins, prepared from Ura-DNA and Me-DNA, respectively, with calf thymus chromosomal protein by salt gradient dialysis, cell extracts released all the Ura but only about half of the 3-MeAde residues, although both these chromatins were degraded by micrococcal nuclease until about half of the nucleotides became acid soluble. The activities of Ura-DNA and 3-MeAde-DNA glycosylase of xeroderma pigmentosum cells were similar to those of normal cells.

Chromatin structure interferes with excision of abnormal bases from DNA.

Cell-free extracts of human lymphoblastoid cells NL3 excised almost all uracil residues from free DNA with misincorporated dUMP, but only about half the uracil residues from nuclei, chromatin and reconstituted chromatin with dUMP-misincorporated DNA. This difference in susceptibility to uracil-DNA glycosylase of free and complexed DNAs was similar to the difference in susceptibility of free and complexed methylated DNAs to 3-methyladenine-DNA glycosylase. Methylated poly(dA-dT) was also protected by formation of complexes with calf thymus chromosomal proteins. It seems that the nucleosome structure prevents the action of DNA glycosylases. The very high sensitivity of PBS1 phage DNA, which contains uracil as a natural component, in complexes with calf thymus chromosomal proteins as well as in the free form [1] was confirmed. This high sensitivity seems ascribable to the high uracil content of PBS1 DNA. Methylated nucleosome monomers and dimers, and reconstituted nucleosome monomers containing methylated DNA of about 150 bp length, were considerably more resistant to 3-methyladenine-DNA glycosylase than chromatin reconstituted from methylated DNA of longer chain length. This may be due to the lower proportion of linker regions of free form stretches of the DNA chain in nucleosome oligomers.

Longitudinal follow-up study of adenoviral vector-mediated gene transfer of dopamine D2 receptors in the striatum in young, middle-aged, and aged rats: a positron emission tomography study.

Overexpression of dopamine D(2) receptors by adenoviral vector-mediated gene transfer in the rat striatum was evaluated by positron emission tomography in vivo and by ex vivo autoradiography in 5-, 13-, and 24-month-old Fischer 344 rats. Each rat had hemilateral gene transfer of D(2) receptors mediated by adenoviral vectors (AdCMV.DopD(2)R) in the striatum with contralateral striatal injection of control vectors (AdCMV.LacZ). At day 2 or 3 after vector injection positron emission tomography or ex vivo autoradiography was performed. The binding potential of a radiolabeled D(2) receptors ligand, [11C]raclopride, was significantly higher in the D(2) receptors gene-transferred striatum than the control side in each age group at a similar degree. The binding potential in the AdCMV.DopD(2)R-injected striatum of 24-month-old rats was similar to that in the AdCMV.LacZ-injected striatum of 5-month-old rats (0.99+/-0.14 versus 0.91+/-0.08). A significant age-associated decrease of the binding potential of [11C]raclopride was found in the control vector-injected side, and a significant increase of the binding potential in the adenoviral vector-injected side in all three age groups, suggesting no aging effect on the overexpression of D(2) receptors. A group of rats underwent follow-up assessment by positron emission tomography. The overexpression of D(2) receptors decreased with time in all three groups; however, the decrease rate of the D(2) receptors expression was significantly smaller in the 24-month-old group than in the 5-month-old group. We confirmed that the adenoviral vector-mediated gene transfer of D(2) receptors compensated the decreased density of striatal D(2) receptors in the 24-month-old rats up to the level in the control striatum of 5-month-old rats, and the decrease rate of the overexpression was significantly smaller in aged rats.

Feasibility of fluorine-18-fluorophenylalanine for tumor imaging compared with carbon-11-L-methionine.

UNLABELLED: L-[methyl-11C]methionine (11C-Met) is a useful tracer for tumor imaging with PET. The drawbacks include a short half-life and high physiological accumulation in abdominal organs. To overcome these shortfalls, the feasible use of [18F]fluorophenylalanine (18F-Phe), which shares the same amino acid transport system with Met, for tumor imaging was examined. METHODS: The time course of tissue distribution of 18F-Phe and the tumor uptake response to radiotherapy were compared with 14C-Met and [3H] thymidine (3H-Thd) in the rat AH109A tumor model. Intratumoral distribution of 18F-Phe was compared with 14C-Met and 14C-Thd using double-tracer macroautoradiography (ARG). We also evaluated whole-body ARG. RESULTS: Tumor uptake of 18F-Phe peaked at 60 min postinjection and was higher than that of the liver, intestine and kidney but lower than the pancreas. Tumor uptake of 18F-Phe was similar to that of 14C-Met. Tumor-to-blood and tumor-to-muscle ratios were higher in 14C-Met compared with that of 18F-Phe because of the rapid blood clearance of 14C-Met. With whole-body ARG, the tumor was clearly visualized with high contrast. Radiotherapeutic response of tumor uptake of 18F-Phe was as rapid as that with 14C-Met and with 3H-Thd. Intratumoral distribution of 18F-Phe and 14C-Met were identical, and 18F-Phe and 14C-Thd were similar. CONCLUSION: Fluorine-18-Phe seems to be a potentially useful amino acid tracer for tumor imaging with a longer half-life than 11C, with higher tumor contrast in the abdomen than Met and a similar sensitive response to radiotherapy.

Re-evaluation of amino acid PET studies: can the protein synthesis rates in brain and tumor tissues be measured in vivo?

The significance of L-[methyl-11C]methionine (11C-Met), L-[1-11C]leucine (11C-Leu) and L-2-[18F]fluorotyrosine (18F-Tyr) for measuring protein synthesis rates in the brain and in tumors by PET was re-evaluated. Tissue uptake and protein incorporation of 3H-Met, 14C-Leu and 18F-Tyr were investigated in mice bearing the FM3A mammary carcinoma. In the control group, the uptake of all three tracers in the brain and FM3A and their incorporation into the acid-precipitable fraction (APF) increased over 60 min. When the protein synthesis in vivo was inhibited by cycloheximide, the incorporation of all three tracers into the APF was significantly reduced to 6%-32% and 3%-11% of the control in the brain and FM3A, respectively. Under these conditions, total uptake of 14C-Leu in the brain and FM3A decreased rapidly, and most of the 14C in the APF was detected as proteins. On the other hand, 3H-Met and 18F-Tyr uptake continued to increase, and significant amounts of radioactivity were incorporated into nonprotein materials. In mice given ouabain to inhibit amino acid transport, total uptake of all three amino acids by FM3A was reduced to 67%-74% of the control 5 min postinjection. These results demonstrate that uptake of the three amino acids is affected by alterations in the amino acid transport system in the brain and tumor tissues, but that only 14C-Leu uptake reflects protein synthesis rates.

Tracer feasibility for monitoring tumor radiotherapy: a quadruple tracer study with fluorine-18-fluorodeoxyglucose or fluorine-18-fluorodeoxyuridine, L-[methyl-14C]methionine, [6-3H]thymidine, and gallium-67.

In a rat AH109A tumor model, metabolic tracers for glucose, amino acid, and nucleic acid metabolisms (2-deoxy-2-[18F]fluoro-D-glucose (18FDG), L-[methyl-14C]methionine (14C-Met), [6-3H]thymidine (3H-Thd), and 2'-deoxy-5-[18F]fluorouridine (18FdUrd], and the conventional radionuclide 67Ga-citrate were used to assess the feasibility of monitoring tumor radiotherapy using a quadruple tracer technique. Two combinations of four tracers (18FDG or 18FdUrd, 14C-Met, 3H-Thd and 67Ga) were compared in a time-course study after single-dose irradiation (20 Gy) and were also used in a dose-dependency study performed 6 days after 5, 10, 15, or 20 Gy of irradiation. Fluorine-18-FDG showed a large change in uptake and a steady response to radiotherapy. Fluorodeoxyuridine showed a rapid decrease after radiotherapy, but the range of change in uptake was narrow. Gallium-67 could not detect tumor response early after treatment, but showed a marked change in uptake later. [6-3H]Thd and 14C-Met showed a rapid response to irradiation and a high sensitivity for monitoring radiotherapy, suggesting that they may be feasible for PET studies.

Selective 2-[18F]fluorodopa uptake for melanogenesis in murine metastatic melanomas.

The relationship between 3,4-dihydroxy-2-[18F]fluoro-L-phenylalanine (2-[18F]FDOPA) uptake and melanogenesis was studied using mice bearing two B16 melanomas: B16-F1 has a higher melanin synthesis ability and a slower growing rate than the higher metastatic B16-F10. A significantly higher 2-[18F]FDOPA uptake by B16-F1 than by B16-F10 and a reverse relationship for the uptake of [14C] 2-deoxy-2-fluoro-D-glucose and [3H]thymidine were observed 1 hr postinjection. F1-to-F10 ratios of both the 2-[18F]FDOPA uptake and the acid-insoluble radioactivity increased to about 5 at 6 hr, which paralleled the melanin content. FM3A mammary carcinoma showed a 2-[18F]FDOPA uptake similar to the B16-F10 but without the acid-insoluble radioactivity. With D,L-DOPA loading, a 55% decreased uptake by FM3A 1 hr postinjection was significantly greater than the 20% reduction in both melanomas. O-Methylated 2-[18F]FDOPA was a predominant acid-soluble metabolite in all tumors. Whole-body autoradiography discriminated the two melanomas clearly. 2-[18F]FDOPA may be a promising tracer for the selective imaging of melanogenesis.

Comparison of L-[1-11C]methionine and L-methyl-[11C]methionine for measuring in vivo protein synthesis rates with PET.

To evaluate the feasibility of using either L-[1-11C]-methionine or L-[methyl-11C]methionine for measuring protein synthesis rates by positron emission tomography (PET) in normal and neoplastic tissues, distribution and metabolic studies with 14C- and 11C-labeled methionines were carried out in rats bearing Walker 256 carcinosarcoma. The tissue distributions of the two 14C-labeled methionines were similar except for liver tissue. Similar distribution patterns were observed in vivo by PET using 11C-labeled methionines. The highest 14C incorporation rate into the protein-bound fraction was found in the liver followed by tumor, brain, and pancreas. The incorporation rates in liver and pancreas were different for the two methionines. By chloroform-methanol fractionation of these four tissues, in liver significantly different amounts of 14C were observed in macromolecules. Also in brain tissue slight differences were found. By HPLC analyses of the protein-free fractions of plasma, tumor, and brain tissue at 60 min after injection, for both methionines several 14C-labeled metabolites in different amounts, were detected. About half of the 14C-labeled material in the protein-free fraction was found to be methionine. In these three tissues the amount of nonprotein metabolites and [14C]bicarbonate amount ranged from 10% to 17% and 12% to 15% for L-[1-14C]methionine and L-[methyl-14C]methionine, respectively. From these results it can be concluded that the minor metabolic pathways have to be investigated in order to quantitatively model the protein synthesis by PET.

Metabolic studies with L-[1-14C]tyrosine for the investigation of a kinetic model to measure protein synthesis rates with PET.

To evaluate a kinetic model for measuring protein synthesis rates by positron emission tomography (PET) in neoplastic and normal tissue, metabolic studies with L-[1-14C]tyrosine were carried out. As an animal model, rats bearing Walker 256 carcinosarcoma were used. Within 60 min after injection, several metabolic parameters were measured. The highest radioactivity uptake, expressed as the differential absorption ratio, was found in pancreas, followed by liver, tumor, and brain. A rapid decarboxylation was observed during the first 15 min. After 60 min, 7.4% of the total injected 14C was expired as 14CO2. In plasma a significant amount of [14C]bicarbonate was detected, but in tissue the amount was negligible. Protein incorporation increased with time. The incorporation rate was the highest in the liver followed by pancreas, tumor, and brain tissues. At 60 min after injection, more than approximately 80% of the 14C in tissue was protein bound. In plasma after a rapid clearance during the first 15 min, the total 14C level increased rapidly and paralleled the increase of protein-bound 14C. As nonprotein [14C]metabolites, in plasma, tumor and brain tissues, p-hydroxyphenylpyruvic acid, p-hydroxyphenyllactic acid, and unidentified metabolites were observed by high performance liquid chromatography. The formation of 14C-labeled 3,4-dihydroxyphenylalanine was found to be negligible. The total amount of these nonprotein metabolites increased with time. At 60 min after injection the percentages of the total nonprotein metabolites and [14C]bicarbonate were only 5.0%, 1.9%, and 3.7% in plasma, tumor and brain tissue, respectively. From our data it is concluded that [11C]carboxylic-labeled tyrosine would be a suitable radiopharmaceutical for measuring protein synthesis rates in neoplastic and normal tissue by PET.