A Global Synthesis Inversion Analysis of Recent Variability in CO2 Fluxes Using GOSAT and In Situ Observations.

The precise contribution of the two major sinks for anthropogenic CO2 emissions, terrestrial vegetation and the ocean, and their location and year-to-year variability are not well understood. Top-down estimates of the spatiotemporal variations in emissions and uptake of CO2 are expected to benefit from the increasing measurement density brought by recent in situ and remote CO2 observations. We uniquely apply a batch Bayesian synthesis inversion at relatively high resolution to in situ surface observations and bias-corrected GOSAT satellite column CO2 retrievals to deduce the global distributions of natural CO2 fluxes during 2009-2010. Our objectives include evaluating bottom-up prior flux estimates, assessing the value added by the satellite data, and examining the impacts of inversion technique and assumptions on posterior fluxes and uncertainties. The GOSAT inversion is generally better constrained than the in situ inversion, with smaller posterior regional flux uncertainties and correlations, because of greater spatial coverage, except over North America and high-latitude ocean. Complementarity of the in situ and GOSAT data enhances uncertainty reductions in a joint inversion; however, spatial and temporal gaps in sampling still limit the ability to accurately resolve fluxes down to the sub-continental scale. The GOSAT inversion produces a shift in the global CO2 sink from the tropics to the north and south relative to the prior, and an increased source in the tropics of ~2 Pg C y-1 relative to the in situ inversion, similar to what is seen in studies using other inversion approaches. This result may be driven by sampling and residual retrieval biases in the GOSAT data, as suggested by significant discrepancies between posterior CO2 distributions and surface in situ and HIPPO mission aircraft data. While the shift in the global sink appears to be a robust feature of the inversions, the partitioning of the sink between land and ocean in the inversions using either in situ or GOSAT data is found to be sensitive to prior uncertainties because of negative correlations in the flux errors. The GOSAT inversion indicates significantly less CO2 uptake in summer of 2010 than in 2009 across northern regions, consistent with the impact of observed severe heat waves and drought. However, observations from an in situ network in Siberia imply that the GOSAT inversion exaggerates the 2010-2009 difference in uptake in that region, while the prior CASA-GFED model of net ecosystem production and fire emissions reasonably estimates that quantity. The prior, in situ posterior, and GOSAT posterior all indicate greater uptake over North America in spring to early summer of 2010 than in 2009, consistent with wetter conditions. The GOSAT inversion does not show the expected impact on fluxes of a 2010 drought in the Amazon; evaluation of posterior mole fractions against local aircraft profiles suggests that time-varying GOSAT coverage can bias estimation of flux interannual variability in this region.

Clinical features of a new disease concept, IgG4-related thyroiditis.

OBJECTIVES: Immunoglobulin (Ig)G4-related disease is a recently proposed systemic disorder that includes autoimmune pancreatitis (AIP), Mikulicz's disease, and various other organ lesions. In the present retrospective study, we examined whether thyroid lesions should also be included in IgG4-related disease (Ig4-RD) under the new term IgG4-related thyroiditis. METHOD: We enrolled 114 patients with Ig4-RD, including 92 patients with AIP, 15 patients with Mikulicz's disease, and seven patients with IgG4-related cholangitis, and analysed clinical findings, function, serum values of activity markers, computed tomography (CT) images, and histology of the thyroid gland. RESULTS: Among the 22 patients (19%) in our cohort who were found to have hypothyroidism [thyroid stimulating hormone (TSH) > 4 mIU/L], 11 patients had clinical hypothyroidism [free thyroxine (FT4) < 1 ng/dL] and 11 patients had subclinical hypothyroidism (FT4 ≥ 1 ng/dL). Serum concentrations of IgG, IgG4, circulating immune complex (CIC), and ß2-microglobulin (ß2-MG) were significantly higher in the hypothyroidism group compared with the remaining 92 euthyroid patients, and serum C3 concentration was significantly lower. After prednisolone treatment, TSH values had decreased significantly (p = 0.005) in this group and FT4 values had increased significantly (p = 0.047). CT images showed that the thyroid glands of patients with clinical hypothyroidism had a significantly greater volume than those of the euthyroid and other groups. Pathological analysis of one resected thyroid gland disclosed a focused lesion with infiltration of lymphocytes and IgG4-bearing plasma cells and loss of thyroid follicles. CONCLUSIONS: Thyroid lesions associated with hypothyroidism can be considered as a new disease termed IgG4-related thyroiditis. Awareness of this condition should lead to appropriate corticosteroid treatment that may prevent progression to a fibrous state.

Structural basis for the altered drug sensitivities of non-small cell lung cancer-associated mutants of human epidermal growth factor receptor.

The epidermal growth factor receptor (EGFR) has an essential role in multiple signaling pathways, including cell proliferation and migration, through extracellular ligand binding and subsequent activation of its intracellular tyrosine kinase (TK) domain. The non-small cell lung cancer (NSCLC)-associated EGFR mutants, L858R and G719S, are constitutively active and oncogenic. They display sensitivity to TK inhibitors, including gefitinib and erlotinib. In contrast, the secondary mutation of the gatekeeper residue, T790M, reportedly confers inhibitor resistance on the oncogenic EGFR mutants. In this study, our biochemical analyses revealed that the introduction of the T790M mutation confers gefitinib resistance on the G719S mutant. The G719S/T790M double mutant has enhanced activity and retains high gefitinib-binding affinity. The T790M mutation increases the ATP affinity of the G719S mutant, explaining the acquired drug resistance of the double mutant. Structural analyses of the G719S/T790M double mutant, as well as the wild type and the G719S and L858R mutants, revealed that the T790M mutation stabilizes the hydrophobic spine of the active EGFR-TK conformation. The Met790 side chain of the G719S/T790M double mutant, in the apo form and gefitinib- and AMPPNP-bound forms, adopts different conformations that explain the accommodation of these ligands. In the L858R mutant structure, the active-site cleft is expanded by the repositioning of Phe723 within the P-loop. Notably, the introduction of the F723A mutation greatly enhanced the gefitinib sensitivity of the wild-type EGFR in vivo, supporting our hypothesis that the expansion of the active-site cleft results in enhanced gefitinib sensitivity. Taken together, our results provide a structural basis for the altered drug sensitivities caused by distinct NSCLC-associated EGFR mutations.

Effect of short-term school closures on the H1N1 pandemic in Japan: a comparative case study.

PURPOSE: The 2009 worldwide influenza A/H1N1 pandemic particularly affected younger people, including schoolchildren. We assessed the effects of class/school closure during the pandemic on the spread of H1N1 infection in Japan. METHODS: We prospectively monitored 2,141 schoolchildren in 57 classes at two elementary schools and two junior high schools in Japan, and evaluated the effects of class/school closures on the spread of H1N1 using descriptive epidemiological methods. RESULTS: The cumulative rate of H1N1 infection among these children was 40.9% (876 children). There was a total of 53 closures of 40 classes, including school closures, during the pandemic. Time-course changes in the epidemic curve showed that school closure reduced the following epidemic peak more than class closure. A Poisson regression model showed that a longer duration of closure was significantly related to decreased H1N1 occurrence after the resumption of classes. CONCLUSIONS: School closure more effectively inhibits subsequent epidemic outbreaks than class closure. Longer school closures are effective in reducing the spread of infection, and school closure should be implemented as early as possible.

A novel heterophilic antibody interaction involves IgG4.

IgG4 has been implicated in a diverse set of complex pathologies - e.g. autoimmune pancreatitis (AIP), idiopathic membranous nephropathy - and carries unique features including lack of activation of the classical complement pathway and a dynamic Fab-arm exchange. We recently showed that the rheumatoid factor (RF)-like activity of IgG4 is achieved through a hitherto unknown, Fc-Fc (and not Fab-Fc as is the case in classical RF; CRF) interaction; hence the name, novel RF (NRF). Here, we further explore the resemblance/difference between CRF and NRF. As heterophilic interactions of human IgM RF (CRF) are well known, we checked whether this is the case for IgG4. Human IgG4 showed variable reactivity to animal IgGs: reacting intensely with rabbit and mouse IgGs, but weakly with others. The binding to rabbit IgG was not through the Fab (as in CRF) but via the Fc piece, as was recently shown for human IgG (NRF). This binding correlates with the IgG4 concentration per se and could therefore be of diagnostic usage and incidentally explain some observed interferences in biological assays. In conclusion, here is defined a novel heterophilic antibody interaction and is established the universality of the unique Fc-Fc binding, both involving IgG4.

Pulmonary involvement of autoimmune pancreatitis.

BACKGROUND: A wide variety of systemic lesions have been seen in patients with autoimmune pancreatitis. The pulmonary involvement of autoimmune pancreatitis was analysed to clarify the clinicopathological features of pulmonary lesions in comparison with pulmonary sarcoidosis. MATERIALS AND METHODS: Nineteen patients had autoimmune pancreatitis and eight had pulmonary sarcoidosis. The symptoms, laboratory data, chest computed tomography, Gallium-67 scintigraphy, pulmonary function testing and bronchoscopy findings, including the histological IgG4-immunostaining and IgG subclasses in the bronchoalveolar lavage in autoimmune pancreatitis, were collected to compare them with pulmonary sarcoidosis. RESULTS: The serum total protein, IgG and IgG4 levels were found to be significantly elevated in comparison with pulmonary sarcoidosis. In autoimmune pancreatitis, 17 patients showed bilateral hilar lymphadenopathy, while eight showed pulmonary nodules on chest computed tomography. Eighteen of 19 patients on Gallium-67 scintigraphy showed accumulation spots in either the hilar or mediastinal lymph nodes. Six patients with pulmonary nodules demonstrated accumulation spots in the corresponding lesions on chest computed tomography. All eight patients with pulmonary sarcoidosis showed accumulation spots in either the hilar or mediastinal lymph nodes. Bronchoalveolar lavage IgG4 in autoimmune pancreatitis showed a significant increase in comparison with pulmonary sarcoidosis. The histological findings obtained by a transbronchial lung biopsy showed the infiltration of lymphocytes and plasma cells in the thickened interstitum and alveoli with IgG4-positive plasma cell infiltration in patients with autoimmune pancreatitis. CONCLUSION: IgG4 in the bronchoalveolar lavage was seen at remarkably increased levels and IgG4-positive plasma cells were identified in the pulmonary lesions of patients with autoimmune pancreatitis.

Central airway stenosis in a patient with autoimmune pancreatitis.

Autoimmune pancreatitis is a unique form of chronic pancreatitis characterised by a high-serum immunoglobulin (Ig)G4 concentration involving various extra pancreatic lesions. A 63-yr-old female with autoimmune pancreatitis complained of cough. Chest computed tomography revealed an irregular stenosis of the central airway, lung hilar and mediastinal lymph node swelling, and a marked thickness of the bronchovascular bundle. Bronchoscopic examination revealed an irregular tracheobronchial stenosis accompanied with an oedematous mucosa and engorged vessels. Lung hilar and mediastinal lymph node swelling, central airway stenosis and bronchoscopic findings remarkably resembled those of sarcoidosis. Bronchial biopsy specimens demonstrated diffuse infiltrations of plasma cells, lymphocytes and eosinophils with fibrosis. Immunostaining showed infiltration of several IgG4-positive plasma cells. The patient was treated with oral prednisolone at 1 mg x kg(-1) x day(-1) for pancreatic lesions. A month later, the lung lesions, including central airway stenosis, lung hilar and mediastinal lymph node swelling, and bronchovascular bundle thickness, had dramatically improved along with improvement of pancreatitis, thus indicating a close association between the two conditions. This is the first report of a patient with autoimmune pancreatitis showing central airway stenosis similar to that of sarcoidosis.

Usefulness of TC-99M GSA liver scintigraphy for the evaluation of liver regeneration in donors after living-donor liver transplantation.

BACKGROUND AND AIMS: We evaluated the impact of steatosis on regeneration and function of the remnant liver by using technetium-99m-diethylenetriaminepentaacetic acid-galactosyl human serum albumin scintigraphy. METHODS: Twelve living donors were classified into groups with or without mild hepatic steatosis according to the liver-to-spleen attenuation ratio on computed tomography: six donors had a ratio > or = 1.2 (control group) and six had a ratio < 1.20 (fatty liver group). Scintigraphy was performed to determine the hepatic uptake ratio of the tracer (corrected for disappearance from the blood) and the maximum removal rate of the tracer by hepatocytes as parameters of the hepatic functional reserve. RESULTS: The fatty liver group had a significantly lower corrected hepatic uptake ratio and removal rate compared with the control group at 6 and 12 months after partial hepatectomy. The regenerated liver volume estimated by scintigraphy did not differ significantly between the two groups at any time. CONCLUSIONS: Because donors with mild hepatic steatosis showed impaired liver regeneration at 1 year after partial hepatectomy, management of these donors requires more care.

Usefulness of TC-99M GSA liver scintigraphy for the assessment of recurrent hepatitis C after living-donor liver transplantation: a case report.

BACKGROUND AND AIMS: Recurrence of hepatitis C after living-donor liver transplantation was investigated using technetium-99m-diethylenetriaminepentaacetic acid-galactosyl human serum albumin (Tc-99m-GSA) liver scintigraphy. METHODS: A 55-year-old woman with cirrhosis due to chronic hepatitis C virus (HCV) infection underwent liver transplantation with a graft from her husband. Scintigraphy was used to determine the hepatic uptake ratio of the tracer corrected for disappearance from the blood, as well as the maximal removal rate of the tracer by hepatocytes, as parameters of hepatic functional reserve. RESULTS: Conventional liver function parameters and the graft volume (computed tomography) were almost unchanged up to 18 months after transplantation. Serum HCV RNA was elevated from 3 months after transplantation, and was twofold higher at 12 months compared with 6 months. At 18 months postoperatively, liver biopsy showed an increase of histologic activity, and there was also evidence of recurrent hepatitis C. The corrected hepatic uptake ratio and maximal removal rate were decreased at 3 months postoperatively, and thereafter remained low. CONCLUSIONS: The decrease of scintigraphic parameters at 3 months after transplantation suggested recurrent hepatitis C affecting the graft. Tc-99m-GSA liver scintigraphy is a useful noninvasive method for evaluating graft functional reserve.

Diffusion-weighted imaging for predicting new compression fractures following percutaneous vertebroplasty.

BACKGROUND: Percutaneous vertebroplasty (PVP) is a technique that structurally stabilizes a fractured vertebral body. However, some patients return to the hospital due to recurrent back pain following PVP, and such pain is sometimes caused by new compression fractures. PURPOSE: To investigate whether the apparent diffusion coefficient (ADC) of adjacent vertebral bodies as assessed by diffusion-weighted imaging before PVP could predict the onset of new compression fractures following PVP. MATERIAL AND METHODS: 25 patients with osteoporotic compression fractures who underwent PVP were enrolled in this study. ADC was measured for 49 vertebral bodies immediately above and below each vertebral body injected with bone cement before and after PVP. By measuring ADC for each adjacent vertebral body, ADC was compared between vertebral bodies with a new compression fracture within 1 month and those without new compression fractures. In addition, the mean ADC of adjacent vertebral bodies per patient was calculated. RESULTS: Mean preoperative ADC for the six adjacent vertebral bodies with new compression fractures was 0.55 x 10(-3) mm(2)/s (range 0.36-1.01 x 10(-3) mm(2)/s), and for the 43 adjacent vertebral bodies without new compression fractures 0.20 x 10(-3) mm(2)/s (range 0-0.98 x 10(-3) mm(2)/s) (P < 0.001). Mean preoperative ADC for the six patients with new compression fractures was 0.55 x 10(-3) mm(2)/s (range 0.21-1.01 x 10(-3) mm(2)/s), and that for the 19 patients without new compression fractures 0.17 x 10(-3) mm(2)/s (range 0.01-0.43 x 10(-3) mm(2)/s) (P < 0.001). CONCLUSION: The ADC of adjacent vertebral bodies as assessed by diffusion-weighted imaging before PVP might be one of the predictors for new compression fractures following PVP.

Sensitivity studies for space-based measurement of atmospheric total column carbon dioxide by reflected sunlight.

The feasibility of making space-based carbon dioxide (CO2) measurements for global and regional carbon-cycle studies is explored. With the proposed detection method, we use absorption of reflected sunlight near 1.58 microm. The results indicate that the small (degrees 1%) changes in CO2 near the Earth's surface are detectable provided that an adequate sensor signal-to-noise ratio and spectral resolution are achievable. Modification of the sunlight path by scattering of aerosols and cirrus clouds could, however, lead to systematic errors in the CO2 column retrieval; therefore ancillary aerosol and cloud data are important to reduce errors. Precise measurement of surface pressure and good knowledge of the atmospheric temperature profile are also required.

Diffusion tensor magnetic resonance imaging of disruption of regional white matter in schizophrenia.

Diffusion tensor imaging provides a new approach for quantifying anisotropic diffusion of white matter in vivo. We used this technique to investigate subtle disruption of regional white matter in schizophrenia. Twelve patients with schizophrenia were compared with 11 healthy controls. Psychotic symptoms were assessed using the Positive and Negative Syndrome Scale. A significant fractional anisotropy (FA) reduction was found in all white matter regions bilaterally in schizophrenic patients. Higher FA of left frontal white matter correlated significantly with higher dosage of antipsychotic medication. These findings support the view that the pathological process is a distortion of the central nervous system myelination affecting the whole white matter. Our findings also show the effects of antipsychotics on the white matter in the left frontal region in schizophrenia.

Potential tumor-targeting peptide vector of histidylated oligolysine conjugated to a tumor-homing RGD motif.

We have developed a potential tumor-targeting peptide vector (cRGD-hK) that is intended to be systemically and repeatedly administered to patients with advanced solid tumors. The peptide vector of 36 l-amino acid residues, CRGDCF(K[H-]KKK)6, comprises a tumor-homing RGD motif, a DNA-binding oligolysine, and histidyl residues to facilitate the delivery into the cytosol. Using cytomegalovirus-driven luciferase expression plasmids as a reporter, we tested the transfection efficiency of cRGD-hK in hepatoma and pancreatic cancer cell lines. Transfection with the cRGD-hK/plasmid complexes (molar ratio 4000:1) was inhibited by 50 nM bafilomycin A1, an inhibitor of the vacuolar ATPase endosomal proton pump, or 10 microM cycloRGDfV, an integrin alphavbeta3 antagonist, indicating that the three elements of cRGD-hK could function as expected, at least in vitro. In nude mice bearing tumors created by subcutaneous inoculation, luciferase activity in the tumor tissues 48 hours after the injection of the cRGD-hK/plasmid complexes through the tail vein (20 microg plasmids per mouse) was significantly higher than that in the lung, kidney, and spleen, but only slightly higher than that in the liver. Although the latter difference was small, we propose a potential nonviral gene therapy for advanced solid tumors through use of the tumor-targeting peptide vector.

Hepatocarcinogenesis inhibition by caffeine in ACI rats treated with 2-acetylaminofluorene.

The inhibitory effects of caffeine have been demonstrated on the development of various organs in animals. The purpose of the present study was to examine the inhibitory effect of caffeine on hepatocarcinogenesis and to determine the responsive dose of caffeine on hepatocarcinogenesis in young male ACI rats. Animals given a diet containing 2-acetylaminofluorene (2-AAF) for 12 weeks and then a basal diet and tap water containing caffeine for 18 weeks showed statistically significant decreases in the incidence, multiplicity (the number of hepatic tumors per rat) and histological grade compared with rats fed a diet containing carcinogen for 12 weeks followed by tap water alone. Dose-dependent inhibition of hepatocarcinogenesis by caffeine was also seen. The inhibitory effect of caffeine on hepatocarcinogenesis in rats was found when caffeine was administered during the initiation phase.

Insulin and somatostatin releasing islet cell tumor caused hypoglycemia.

We report a hypoglycemic case with normal insulin levels, which was caused by an islet cell tumor that was releasing insulin and somatostatin. A fasting test suggested the over secretion of insulin. Moreover, this hypoglycemia was enhanced by the inhibitory effect of somatostatin on the secretion of insulin counter-regulatory hormones, such as glucagon, in addition to the autonomous secretion of insulin from the tumor. In cases of hypoglycemia with apparently normal insulin levels, the measurement of somatostatin and various provocative tests are recommended. Arterial stimulation venous sampling (ASVS) was useful to detect the location of this functioning islet cell tumor.