Case report: A case of piriformis pyomyositis and pyogenic sacroiliitis due to non-typhoidal Salmonella bacteremia in an immunocompetent healthy adult.

Non-typhoidal Salmonella (NTS) rarely causes bacteremia and subsequent focal infections as an extraintestinal complication, even in immunocompetent adults. A 25-year-old man was hospitalized for several days with difficulty moving due to fever, acute buttock pain, and shivering. He had no recent or current respiratory symptoms and no clear gastrointestinal symptoms. Physical examination revealed mild redness around the left buttock and difficulty raising the left lower extremity due to pain, in addition to which blood tests showed high levels of inflammatory markers. His clinical course and laboratory findings suggested sepsis, and magnetic resonance imaging revealed a high-intensity area in the left piriformis muscle on diffusion-weighted imaging; therefore, acute piriformis pyomyositis was strongly suggested. Cephazolin was started upon hospitalization; however, blood and stool cultures proved positive for NTS, and the antibiotics were changed to ceftriaxone. Follow-up MRI showed a signal in the left piriformis muscle and newly developed left pyogenic sacroiliitis. On the 25th hospital day, a colonoscopy was performed to identify the portal of entry for bacteremia, which revealed a longitudinal ulcer in the sigmoid colon in the healing process. His buttock pain gradually improved, and the antibiotics were switched to oral levofloxacin, which enabled him to continue treatment in an outpatient setting. Finally, the patient completed seven weeks of antimicrobial therapy and returned to daily life without leaving any residual disability. Invasive NTS infection due to bacteremia is rare among immunocompetent adults. Piriformis pyomyositis and subsequent pyogenic sacroiliitis should be added to the differential diagnosis of acute febrile buttock pain. In the case of NTS bacteremia, the entry site must be identified for source control. Additionally, the background of the host, especially in such an immunocompetent case, needs to be clarified; therefore, the patient should be closely examined.

Suggestive Diagnostic Process in a Case of Multiple Myeloma with Gastrointestinal Immunoglobulin Light-Chain Amyloidosis Accompanied by Protein-Losing Enteropathy.

Multiple myeloma is a type of plasma cell neoplasm that produces monoclonal immunoglobulin. Multiple myeloma is known to cause immunoglobulin light-chain (AL) amyloidosis, which frequently involves the kidney and heart. Bone pain or fractures caused by osteolytic lesions and physical disorders related to renal or cardiac AL amyloidosis are major initial symptoms in multiple myeloma. Multiple myeloma diagnosed from the gastrointestinal symptoms is rare. We report a case of an 80-year-old man with multiple myeloma accompanied by gastrointestinal AL amyloidosis and secondary protein-losing enteropathy. The diagnostic process was suggestive, in that diarrhea and refractory leg edema related to protein-losing enteropathy were the primary symptoms and the trigger for making a sequential diagnosis of gastrointestinal AL amyloidosis and underlying multiple myeloma. This case is highly suggestive, in that multiple myeloma with gastrointestinal AL amyloidosis should be considered one of the background diseases of protein-losing enteropathy.

Evaluation of [(11)C]oseltamivir uptake into the brain during immune activation by systemic polyinosine-polycytidylic acid injection: a quantitative PET study using juvenile monkey models of viral infection.

BACKGROUND: Abnormal behaviors of young patients after taking the anti-influenza agent oseltamivir (Tamiflu®, F. Hoffmann-La Roche, Ltd., Basel, Switzerland) have been suspected as neuropsychiatric adverse events (NPAEs). Immune response to viral infection is suspected to cause elevation of drug concentration in the brain of adolescents. In the present study, the effect of innate immune activation on the brain uptake of [(11)C]oseltamivir was quantitatively evaluated in juvenile monkeys. METHODS: Three 2-year-old monkeys underwent positron emission tomography (PET) scans at baseline and immune-activated conditions. Both scans were conducted under pre-dosing of clinically relevant oseltamivir. The immune activation condition was induced by the intravenous administration of polyinosine-polycytidylic acid (poly I:C). Dynamic [(11)C]oseltamivir PET scan and serial arterial blood sampling were performed to obtain [(11)C]oseltamivir kinetics. Brain uptake of [(11)C]oseltamivr was evaluated by its normalized brain concentration, brain-to-plasma concentration ratio, and plasma-to-brain transfer rate. Plasma pro-inflammatory cytokine levels were also measured. RESULTS: Plasma interleukin-6 was elevated after intravenous administration of poly I:C in all monkeys. Brain radioactivity was uniform both at baseline and under poly I:C treatment. The mean brain concentrations of [(11)C]oseltamivir were 0.0033 and 0.0035% ID/cm(3) × kg, the mean brain-to-plasma concentration ratios were 0.58 and 0.65, and the plasma-to-brain transfer rates were 0.0047 and 0.0051 mL/min/cm(3) for baseline and poly I:C treatment, respectively. Although these parameters were slightly changed by immune activation, the change was not notable. CONCLUSIONS: The brain uptake of [(11)C]oseltamivir was unchanged by poly I:C treatment in juvenile monkeys. This study demonstrated that the innate immune response similar to the immune activation of influenza would not notably change the brain concentration of oseltamivir in juvenile monkeys.

Nurr1 is required for maintenance of maturing and adult midbrain dopamine neurons.

Transcription factors involved in the specification and differentiation of neurons often continue to be expressed in the adult brain, but remarkably little is known about their late functions. Nurr1, one such transcription factor, is essential for early differentiation of midbrain dopamine (mDA) neurons but continues to be expressed into adulthood. In Parkinson's disease, Nurr1 expression is diminished and mutations in the Nurr1 gene have been identified in rare cases of disease; however, the significance of these observations remains unclear. Here, a mouse strain for conditional targeting of the Nurr1 gene was generated, and Nurr1 was ablated either at late stages of mDA neuron development by crossing with mice carrying Cre under control of the dopamine transporter locus or in the adult brain by transduction of adeno-associated virus Cre-encoding vectors. Nurr1 deficiency in maturing mDA neurons resulted in rapid loss of striatal DA, loss of mDA neuron markers, and neuron degeneration. In contrast, a more slowly progressing loss of striatal DA and mDA neuron markers was observed after ablation in the adult brain. As in Parkinson's disease, neurons of the substantia nigra compacta were more vulnerable than cells in the ventral tegmental area when Nurr1 was ablated at late embryogenesis. The results show that developmental pathways play key roles for the maintenance of terminally differentiated neurons and suggest that disrupted function of Nurr1 and other developmental transcription factors may contribute to neurodegenerative disease.

Development of polyclonal antibodies specific to ATP-binding cassette transporters human ABCG4 and mouse Abcg4: site-specific expression of mouse Abcg4 in brain.

In our recent study on seeking new mouse ATP-binding cassette (ABC) transporters of the G subfamily, we succeeded in cloning mouse Abcg4 from a cDNA library of mouse brain, and we characterized the tissue-specific expression and chromosomal localization of the mouse Abcg4 gene. To further characterize the physiological function of mouse Abcg4 protein and to compare its function with that of ABCG2, in the present study, we developed polyclonal antibodies against mouse Abcg4 and established the Abcg4-expression system. To raise antibodies, we selected three different epitope peptides that correspond to the amino acid residues of 46-60, 465-479, and 600-613 in mouse Abcg4 protein. The antibody raised against the epitope encoding the amino acids 46-60 was found to be specific to mouse Abcg4, exhibiting a band with molecular weight of 63,000 on immunoblotting, whereas this band was dose-dependently diminished by adding the corresponding epitope peptide into the immunoblot medium. Use of the antibody for immunoblot detection in mouse normal tissues revealed that the Abcg4 protein is expressed in brain, spleen, and testis. Immunohistochemical studies showed that mouse Abcg4 is site-specifically expressed in the cerebral cortex and medulla of mouse brain. These results suggest that mouse Abcg4 plays a certain physiological role in the brain. It is of importance to note that the sequence of amino acids 46-60 is completely identical between mouse Abcg4 and human ABCG4. Thus, this antibody is applicable to the detection of human ABCG4 as well as mouse Abcg4.

Blood flow dependence of the intratumoral distribution of peripheral benzodiazepine receptor binding in intact mouse fibrosarcoma.

The intratumoral distribution of [(11)C]AC-5216 binding, a novel peripheral benzodiazepine receptor (PBR) ligand, was examined by autoradiography both in vitro and in vivo using a murine fibrosarcoma model. The regional distribution of [(11)C]AC-5216 in a tumor in vivo was significantly heterogeneous; the uptake of [(11)C]AC-5216 was comparatively higher in the outer rim of the tumor and was lower in the central area. In contrast, the images obtained following the injection of [(11)C]AC-5216 with a large amount of nonlabeled PK11195 showed a relatively homogeneous distribution, suggesting that [(11)C]AC-5216 uptake represented specific binding to PBRs. In vitro autoradiograms of [(11)C]AC-5216 binding were also obtained using the section of the fibrosarcoma that was the same as that used to examine in vivo binding. In vitro autoradiographic binding images showed homogeneous distribution, and significant discrepancies of the intratumoral distribution of [(11)C]AC-5216 were observed between in vivo and in vitro images. The in vivo images of [(11)C]AC-5216 uptake, compared with those of [(14)C]iodoantipyrine uptake, obtained by dual autoradiography to evaluate the influence of blood flow revealed the similar intratumoral distributions of both tracers. These results indicate that the delivery process from the plasma to the tumor might be the rate-limiting step for the intratumoral distribution of PBR binding in vivo in a fibrosarcoma model.

Phosphoinositide 3-kinase in nitric oxide synthesis in macrophage: critical dimerization of inducible nitric-oxide synthase.

Phosphoinositide 3-kinase (PI3K) has important functions in various biological systems, including immune response. Although the role of PI3K in signaling by antigen-specific receptors of the adaptive immune system has been extensively studied, less is known about the function of PI3K in innate immunity. In the present study, we demonstrate that macrophages deficient for PI3K (p85alpha regulatory subunit) are impaired in nitric oxide (NO) production upon lipopolysaccharide and interferon-gamma stimulation and thus vulnerable for intracellular bacterial infection such as Chlamydophila pneumoniae. Although expression of inducible nitric-oxide synthase (iNOS) is induced normally in PI3K-deficient macrophages, dimer formation of iNOS protein is significantly impaired. The amount of intracellular tetrahydrobiopterin, a critical stabilizing cofactor for iNOS dimerization, is decreased in the absence of PI3K. In addition, induction of GTP cyclohydrolase 1, a rate-limiting enzyme for biosynthesis of tetrahydrobiopterin, is greatly reduced. Our current results demonstrate a critical role of class IA type PI3K in the bactericidal activity of macrophages by regulating their NO production through GTP cyclohydrolase 1 induction.

Nerve growth factor-induced expression of the GTP cyclohydrolase I gene via Ras/MEK pathway in PC12D cells.

Neurotrophins are essential for the development and survival of the catecholaminergic neurons. GTP cyclohydrolase I (GCH) is the first and rate-limiting enzyme in the biosynthesis of 5,6,7,8-tertahydrobiopterin (BH4), the required cofactor for tyrosine hydroxylase. Previously, we reported that TH requires the Ras/mitogen-activated protein kinase kinase (MEK) pathway for its induction by nerve growth factor (NGF). Here, we examined intracellular signals required for NGF-induced expression of the GCH gene in PC12D cells. The activity of GCH was increased up to 5-fold after the NGF treatment, and the increase was repressed by pretreatment with U0126, an MEK1/2 inhibitor, but not with protein kinase A (PKA), phosphoinositide 3-kinase (PI3K), p38 mitogen-activated protein kinase (MAPK), and c-Jun NH2-terminal kinase (JNK) inhibitors. Induction of GCH mRNA by NGF was also abolished by pretreatment with U0126. The human GCH promoter activity was significantly enhanced by NGF treatment. Deletion analysis showed that the 465-bp 5'-flanking region is responsible for NGF-enhanced promoter activity. These data suggest that the Ras-MEK pathway is required for coordinate expression of the GCH and TH genes induced by neurotrophins.