FDG-PET for the diagnosis of fever of unknown origin: a Japanese multi-center study

Objective

To evaluate the clinical value of 2-[¹⁸F]fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) for the diagnosis of fever of unknown origin (FUO), we performed a Japanese multi-center retrospective survey.

Methods

A total of 81 consecutive patients with FUO who underwent FDG-PET at 6 institutions between July 2006 and December 2007 were retrospectively evaluated. FDG uptake was visually evaluated using a 4-grade scale. The efficacy of FDG-PET for the evaluation of FUO, the provision of additional diagnostic information, the clinical impact on therapeutic decisions (4-grade scale), and the diagnostic performance compared with the final diagnosis were evaluated.

Results

The diagnostic results were analyzed according to 4 groups of final diagnoses: infection, arthritis/vasculitis/autoimmune/collagen disease (A/V), tumor/granuloma (T/G), and other/unknown (O/U). Sensitivity was highest in T/G, followed by infection, A/V and O/U [100%(7/7), 89%(24/27), 65%(11/17), 0%(0/1) respectively]. Clinical impact and mean FDG score showed the same tendency. Additional information was highest in infection followed by T/G, A/V, and O/U [76%(22/29), 75%(6/8), 43%(9/21), 23%(5/22), respectively]. The O/U group showed a high specificity (84%, 16/19) and accurately excluded active focal inflammatory diseases and malignancy. The use of steroids for the treatment of fever seemed to mask the lesions and modified the results, especially in the A/V group (4 false negatives in 8 steroid users out of 21 A/V patients). The prevalence of each disease in each hospital significantly affected the effectiveness of FDG-PET for the diagnosis of FUO. The mean FDG uptake score and additional information (70%, 31/44 vs. 30%, 11/37, respectively) in national hospital (NH) was significantly higher than in university hospitals (UH). A Grade 3 clinical impact, in which the FDG PET results changed the clinical decision, was seen in 50% (22/44) of the patients in the NH group and 13.5% (5/37) of the patients in the UH group. The sensitivity (91%, 30/33; 63%, 12/19) and specificity (60%, 6/10; 86%, 12/14) of the results in the NH and UH groups differed. The total sensitivity was 81% (42/52), specificity was 75% (18/24). The NH group included a large number of cases with infectious diseases (50%, 23/44), while the UH group included a large number of A/V cases (38%, 14/37) and O/U cases (41%, 15/37).

Conclusion

FDG-PET for the diagnosis of FUO provided additional diagnostic information and had a high clinical impact, especially among patients with infectious diseases. It was also helpful in cases with unknown or other miscellaneous diseases by allowing the exclusion of focally active diseases. The prevalence of diseases in hospitals significantly affected the effectiveness of FDG-PET for the diagnosis of FUO. FDG-PET is a useful examination providing various degrees of clinical impact for the management of FUO, depending on the characteristics of the patient and the hospital.     

A case of multifocal fibrosclerosis presenting with chronic subdural hematoma

Multifocal fibrosclerosis(MFS) is a rare disorder of unknown etiology, characterized by chronic inflammation with dense fibrosis and lymphoplasmacytic infiltration into the connective tissue of various organs. Recently, MFS was classified as IgG4-related systemic disease. In this paper, we report a 60-year-old man with no history of head injury presenting with chronic subdural hematoma(CSDH). After surgery, he complained of severe, continuous headache and persistent high-grade fever. Extensive evaluation, including ??Ga scintigraphy suggesting inflammations in various organs, liver needle biopsy showing sclerosing cholangitis, and blood examination showing elevated serum IgG4 levels, led to the diagnosis of MFS. To our knowledge this is the first report of MFS causing CSDH. The mechanism of the formation of CSDH is presumed to involve reactive granular membrane together with exudative subdural collection caused by MFS, which gives rise to minor and repeated bleeding. In this case, oral corticosteroid therapy was dramatically effective in the treatment of the condition.     

Observer variation study of the assessment and diagnosis of incidental colonic FDG uptake

Purpose

The aim of this study was to evaluate the interpretations of incidental colonic 18F-FDG uptake made by 10 experienced readers and to more clearly identify the pattern of suspicious colonic FDG uptake. The potential contributions of delayed FDG-PET scanning and of immune fecal occult blood testing (FOBT) in making a diagnosis were also analyzed.

Materials and methods

Visual interpretations by 10 readers were made for 147 FDG uptake sites from 126 PET scans (cancer, 38 sites; adenoma, 43 sites; and no abnormality, 66 sites) with colonic FDG uptake. Assessments for the early FDG-PET images were (1) FDG uptake pattern, (2) FDG uptake degree, and (3) likelihood of malignancy. For the delayed images, the assessments were (1) change in the FDG uptake position, (2) change in FDG uptake degree, and (3) likelihood of malignancy. The results of FOBT were analyzed independently of the visual interpretations.

Results

Interobserver agreement (κ) was 0.501 for assessing FDG uptake patterns, while agreement on assessing changes in uptake degree and changes in uptake position between early and delayed imaging were low (κ = 0.213–0.229). Logistic regression analysis indicated that ‘FDG uptake patterns’ and ‘FDG uptake degree’ were significantly related to decide on the suspicion of malignancy (p < 0.001) and the final result (p < 0.001). “Small localized” and “large irregular localized” types had a high probability of a lesion regardless of either (1) FDG uptake degree or (2) variation in the uptake between the early and the delayed image. The delayed image decreased false-positive cases for some FDG uptake patterns, but it had little impact on distinguishing clearly between “cancer or adenoma” and “normal”. The addition of FOBT had little impact on the diagnosis.

Conclusion

There was highest agreement among readers with respect to the recognition of specified colonic FDG uptake patterns, and this pattern recognition had the most influence on the diagnosis. “Small localized” and “large irregular localized” types had a high probability of a lesion. The addition of delayed imaging and of FOBT results to the early imaging did not have much impact on the diagnosis.     

Rab GAP cascade regulates dynamics of Ypt6 in the Golgi traffic

The Golgi apparatus functions as the central station of membrane traffic in cells, where newly synthesized proteins moving along the secretory pathway merge with proteins recycled from subsequent membrane organelles such as endosomes. A series of Rab GTPases act consecutively and in concert with the maturation of cis- to-trans cisternae of the Golgi apparatus. Rab GTPases control various steps in intracellular membrane traffic by recruiting downstream effector proteins. Here, we report the dynamics of Ypt6, a yeast member of the Rab GTPase family, which mediates the fusion of vesicles from endosomes at the Golgi apparatus. Ypt6 resides temporarily at the Golgi and dissociates into the cytosol upon arrival of Ypt32, another Rab GTPase functioning in the late Golgi. We found that Gyp6, a putative GTPase-activating protein (GAP) for Ypt6, specifically interacts with Ypt32, most likely as an effector. Disruption of GYP6 or introduction of a Rab–GAP activity-deficient mutation in GYP6 resulted in continual residence of Ypt6 at the Golgi. We propose that Ypt32 acts to terminate endosome-to-Golgi traffic through a Rab–GAP cascade as it does for cis-to-trans intra-Golgi traffic. Simultaneous disruption of GAP for early-acting Rab proteins in the Golgi showed appreciable defects in post-Golgi trafficking, but did not significantly affect cell growth.Rab GTPase cycles between the active, membrane-bound form and the inactive, cytosolic form via the action of intrinsic GTP exchange factor (GEF) and GTPase-activating protein (GAP). Once Rab GTPase is activated and targeted to the membrane, various downstream effectors are recruited onto the membrane to fulfill various intracellular membrane trafficking processes (1). Each Rab GTPase exhibits a unique spatiotemporal localization pattern at a particular membranous compartment to precisely regulate vesicular traffic. Thus, Rab GTPase and its effectors define a compartment’s identity (2, 3).The Rab–GEF cascade consists of sequential regulation of Rab GTPases in which an upstream Rab recruits a GEF for downstream Rab activation. This continuous activation of Rab proteins occurs at several organelles such as endosomes, transport vesicles, and the Golgi apparatus. For example, Rab5 recruits the Mon1–Ccz1 complex, which is a GEF for Rab7 and facilitates Rab5-Rab7 conversion during early to late endosome maturation in yeast and animal cells (4, 5). In the exocytic pathway of the budding yeast Saccharomyces cerevisiae, transition from Ypt1 to Ypt31/32 occurs at the Golgi apparatus by recruitment of Ypt31/32 GEF as a Ypt1 effector (6). Once Ypt31/32 is activated, Sec2, a GEF for Sec4, is recruited onto the membrane to activate Sec4 at post-Golgi transport vesicles (7). Although the Rab–GEF cascade regulates the continuity of different Rab GTPases in such organelles (1), it also potentially creates instability because continuous activation of early Rab GTPase leads to the concomitant existence of two Rab proteins on the same membrane. Recent work has provided evidence for a Rab–GAP cascade, in which a GAP of a former Rab is the effector of subsequent Rab proteins at the Golgi apparatus in yeast (8). Termination of early acting Ypt1 is facilitated by the recruitment of Gyp1, a GAP for Ypt1, through binding to Ypt32 as an effector at a single cisterna of the Golgi.This counter current activity of Rab GTPases could be a main mechanism of compartment maturation (9, 10). Because Rab defines the identity of a membrane compartment through the recruitment of effector proteins, the transition from one Rab to another changes the properties of the membrane where they exist. In the Golgi apparatus, the disruption of the boundary between two Rab proteins would affect cisternal maturation. This appears to be indeed the case in yeast in the transition of an early acting Rab-containing compartment to another containing a late-acting Rab (8). Nevertheless, Gyp1, a GAP responsible for the Rab–GAP cascade in the Golgi, is dispensable for yeast cell growth. Other mechanisms may exist, in which transient contact between two compartments contributes to the maturation of the Golgi apparatus (11).Ypt6, the yeast counterpart of Rab6, has been reported to associate with the Golgi apparatus and regulate the fusion of vesicles from endosomes (12). In mammalian cells, accumulating evidence suggests that Rab6 localizes at the trans-Golgi region and functions in retrograde protein transport and in Golgi structural organization (13, 14). Ypt6 may very well function in the yeast Golgi maintenance. Ypt6 is activated in to the GTP-bound state by the Ric1–Rgp1 GEF complex and associates with the Golgi membrane, where it recruits a tethering factor called the Golgi-associated retrograde protein (GARP) complex (15, 16). S. cerevisiae has eight Rab GAP proteins containing the conserved Tre2-Bub2-Cdc16 (TBC) domain, which provides the catalytic activity toward Rab GTPases. Putative GAP proteins for Ypt6, including Gyp6, have been identified and characterized in vitro (17, 18). However, TBC domain-containing proteins have broad GAP activities toward multiple Rab proteins in contrast to the high specificity between Rab–GEF pairs (19). In the case of Ypt6, not only Gyp6 but also Gyp2 and Gyp8 show in vitro GAP activity toward Ypt6 (20, 21). Thus, the precise mechanisms controlling Ypt6 dynamics and the relationship between multiple Rab GTPases in the Golgi apparatus remain obscure.Here, we report roles of Rab–GAP in regulation of Ypt6 dynamics in S. cerevisiae. We have found that Ypt6 resides at the medial-Golgi and dissociates from the membrane at the onset of Ypt31/32 arrival during maturation. Gyp6, a putative GAP for Ypt6, binds to Ypt32 and is recruited to the membrane, facilitating the dissociation of Ypt6. This counteracting regulation of Ypt6 requires the GAP activity of Gyp6, suggesting that a Rab–GAP cascade defines the membrane traffic from the endosomes to the Golgi apparatus.     

Measuring and modeling the interaction among reward size, delay to reward, and satiation level on motivation in monkeys

Motivation is usually inferred from the likelihood or the intensity with which behavior is carried out. It is sensitive to external factors (e.g., the identity, amount, and timing of a rewarding outcome) and internal factors (e.g., hunger or thirst). We trained macaque monkeys to perform a nonchoice instrumental task (a sequential red-green color discrimination) while manipulating two external factors: reward size and delay-to-reward. We also inferred the state of one internal factor, level of satiation, by monitoring the accumulated reward. A visual cue indicated the forthcoming reward size and delay-to-reward in each trial. The fraction of trials completed correctly by the monkeys increased linearly with reward size and was hyperbolically discounted by delay-to-reward duration, relations that are similar to those found in free operant and choice tasks. The fraction of correct trials also decreased progressively as a function of the satiation level. Similar (albeit noiser) relations were obtained for reaction times. The combined effect of reward size, delay-to-reward, and satiation level on the proportion of correct trials is well described as a multiplication of the effects of the single factors when each factor is examined alone. These results provide a quantitative account of the interaction of external and internal factors on instrumental behavior, and allow us to extend the concept of subjective value of a rewarding outcome, usually confined to external factors, to account also for slow changes in the internal drive of the subject.     

Efficacy of TAK-457, a novel intravenous triazole, against invasive pulmonary Aspergillosis in neutropenic mice.

TAK-457 is an injectable prodrug of TAK-456, which is a novel oral triazole compound with potent antifungal activity. The in vivo efficacy of TAK-457 was evaluated in two models of invasive pulmonary aspergillosis with CDF(1) mice and CBA/J mice with transient neutropenia induced by cyclophosphamide. Against the infection in CDF(1) mice, treatment with 10 mg of TAK-457 and 1 mg of amphotericin B/kg reduced the fungal burden in lungs and rescued all mice. In the infection model with CBA/J mice, TAK-457 at a dose of 10 mg/kg significantly prolonged the survival time of mice, showing significant reduction of lung chitin levels and the plasma beta-D-glucan levels. On the other hand, amphotericin B at 1 mg/kg which was a maximum tolerable dose showed slight but not significant prolongation of survival time of mice, although it also reduced the lung chitin levels and the plasma beta-D-glucan levels to a lower extent but still significantly. These results suggest that TAK-457 is a promising candidate for development for the treatment of invasive aspergillosis in humans.     

On the occurrence and physiological effect of somatostatin in the ciliary ganglion of cats

Somatostatin-like immunoreactive nerve fibers occurred among and around ganglion cells in the form of punctate structures or varicose processes in the cat ciliary ganglion. The density of the fibers varied greatly from region to region and approximately 25% of the whole population of neuronal soma that appeared in a single section were surrounded by immunoreactive fibers. No somatostatin-positive cell bodies were observed. Application of somatostatin to this ganglion in vitro by superfusion induced membrane hyperpolarization in approximately 60% of the neurons examined. The hyperpolarization was preserved in a low Ca/high Mg medium. This response was associated with a decrease in input membrane resistance and was reversed in polarity at nearly --90 mV. The present findings suggest that somatostatin may play a role as a neurotransmitter or modulator in this parasympathetic ganglion.     

An electron microscopic study on VIP-like immunoreactive nerve fibers in the celiac ganglion of guinea pigs

An immuno-electron microscopic study revealed that VIP-like immunoreactive nerve fibers in the celiac ganglion of guinea pigs were characterized by a conspicuously numerous large granular vesicles mixed with small clear vesicles. The immunoreactive materials were localized in the core of the large granular vesicles and a distinct halo was recognized between the core and the limiting membrane of the vesicles. These fibers made numerous axo-dendritic and a few axo-somatic synapses with the post-ganglionic principal neurons and also formed some synapses with vesicle-containing neuronal profiles which are presumably preganglionic axons. The immunoreactive fibers were presynaptic at all these synaptic sites. In addition, some synaptic contacts were found between two adjacent immunoreactive nerve fibers. These findings strongly suggests that VIP might be involved in the ganglionic transmission of the prevertebral ganglia.     

An electron microscopic study on substance P-like immunoreactive nerve fibers in the celiac ganglion of guinea pigs

Substance P-immunoreactive nerve fibers in the celiac ganglion of guinea pigs were revealed with the PAP procedures to contain abundant small clear vesicles mixed with a few large granular vesicles. The immunoreactive materials were localized around cytoplasmic components including vesicles and on the inside of the plasma membrane. The immunoreactive fibers directly apposed to unlabelled dendrites of postganglionic neurons and also to preganglionic axons. Morphological features of synapses could be identified at sites of apposition to unlabelled dendrites: clusters of vesicles in the immunoreactive fibers, intercellular spaces of about 20 nm, and an intermediate density on the postjunctional membrane of unlabelled dendrites. On the other hand, no distinct electron density together with accumulations of vesicles was seen underneath the apposed membrane of unlabelled axons. These findings indicate at the ultrastructural level that substance P-fibers form axo-dendritic synapses on the postganglionic neurons and also suggest the presence of the presynaptic interaction between substance P-fibers and some preganglionic axons in this ganglion.