Organization of feedback projections to mouse primary visual cortex.

Top-down, context-dependent modulation of visual processing has been a topic of wide interest, including in mouse primary visual cortex (V1). However, the organization of feedback projections to V1 is relatively unknown. Here, we investigated inputs to mouse V1 by injecting retrograde tracers. We developed a software pipeline that maps labeled cell bodies to corresponding brain areas in the Allen Reference Atlas. We identified more than 24 brain areas that provide inputs to V1 and quantified the relative strength of their projections. We also assessed the organization of the projections, based on either the organization of cell bodies in the source area (topography) or the distribution of projections across V1 (bias). Projections from most higher visual and some nonvisual areas to V1 showed both topography and bias. Such organization of feedback projections to V1 suggests that parts of the visual field are differentially modulated by context, which can be ethologically relevant for a navigating animal.

Creating and controlling visual environments using BonVision.

Real-time rendering of closed-loop visual environments is important for next-generation understanding of brain function and behaviour, but is often prohibitively difficult for non-experts to implement and is limited to few laboratories worldwide. We developed BonVision as an easy-to-use open-source software for the display of virtual or augmented reality, as well as standard visual stimuli. BonVision has been tested on humans and mice, and is capable of supporting new experimental designs in other animal models of vision. As the architecture is based on the open-source Bonsai graphical programming language, BonVision benefits from native integration with experimental hardware. BonVision therefore enables easy implementation of closed-loop experiments, including real-time interaction with deep neural networks, and communication with behavioural and physiological measurement and manipulation devices.

Spatial readout of visual looming in the central brain of Drosophila.

Visual systems can exploit spatial correlations in the visual scene by using retinotopy, the organizing principle by which neighboring cells encode neighboring spatial locations. However, retinotopy is often lost, such as when visual pathways are integrated with other sensory modalities. How is spatial information processed outside of strictly visual brain areas? Here, we focused on visual looming responsive LC6 cells in Drosophila, a population whose dendrites collectively cover the visual field, but whose axons form a single glomerulus-a structure without obvious retinotopic organization-in the central brain. We identified multiple cell types downstream of LC6 in the glomerulus and found that they more strongly respond to looming in different portions of the visual field, unexpectedly preserving spatial information. Through EM reconstruction of all LC6 synaptic inputs to the glomerulus, we found that LC6 and downstream cell types form circuits within the glomerulus that enable spatial readout of visual features and contralateral suppression-mechanisms that transform visual information for behavioral control.

Ultrasonic measurement of sound velocity fluctuations in biological tissue due to ultrasonic heating and estimation of thermo-physical properties.

PURPOSE: Tissue characterization in terms of the differences in thermo-physical properties of biological tissues was investigated in this study. The objective was to measure the ratio of variation in sound velocity due to ultrasonic heating and to derive the relational expression between the ratio and thermo-physical properties. METHODS: The ratio of sound velocity variation before and after the temperature rise of tissue samples exposed to ultrasound was measured by ultrasonic pulse echo method. The thermo-physical properties were estimated for a tissue-mimicking material and porcine muscle and fat tissues due to theoretical expression. The transducer for heating had a resonance frequency of 3.2 MHz, and the transducer for measurement of sound velocity variation had a resonance frequency of 5.2 MHz. RESULTS: In the phantom study, the measured values of the temperature rise agreed with the values calculated by a finite element method (FEM). The estimated values of the temperature rise from the sound velocity variations of muscle and fat tissues were 0.36 °C and 1.1 °C, respectively. Also, the estimated values of thermo-physical properties agreed with the reference values within an error of 10%. CONCLUSIONS: The thermo-physical properties of the porcine tissues were measured by sound velocity variation due to ultrasonic heating within the safety regulations.

In Vivo Observation of Structural Changes in Neocortical Catecholaminergic Projections in Response to Drugs of Abuse.

Catecholaminergic (dopamine and norepinephrine) projections to the cortex play an important role in cognitive functions and dysfunctions including learning, addiction, and mental disorders. While dynamics of glutamatergic synapses have been well studied in such contexts, little is known regarding catecholaminergic projections, owing to lack of robust methods. Here we report a system to monitor catecholaminergic projections in vivo over the timeframes that such events occur. Green fluorescent protein (GFP) expression driven by tyrosine hydroxylase promoter in a transgenic mouse line enabled us to perform two-photon imaging of cortical catecholaminergic projections through a cranial window. Repetitive imaging of the same axons over 24 h revealed the highly dynamic nature of catecholaminergic boutons. Surprisingly, administration of single high dose methamphetamine (MAP) induced a transient increase in bouton volumes. This new method opens avenues for longitudinal in vivo evaluation of structural changes at single release sites of catecholamines in association with physiology and pathology of cortical functions.

A retrospective analysis of 7 cases of familial mediterranean fever.

BACKGROUND: Familial mediterranean fever (FMF) is a single inherited autoinflammatory disease characterized by periodic fever with relatively short duration of 1 to 3 days and sterile serositis. Although the prevalence rate is highest in the Mediterranean coastal area, a large number of cases have been reported recently by genetic analysis by identification of MEFV (Mediterranean fever) which is responsible gene in Japan too. In outpatient department of rheumatology, diagnosis and treatment of FMF is performed in cases where fever and abdominal pain attack are repeated for a short period of time. PATIENTS AND METHODS: We examined cases in which symptoms considered periodic seizures were repeated, excluding autoimmune diseases, infectious diseases, and malignant tumors. In both cases, genetic analysis is performed as auxiliary diagnosis. RESULTS: Seven cases satisfied the Tel-Hashomer criteria criteria and MEFV gene mutation was detected. Everyone was a female, and half had seizure symptoms at menstruation. Even though there is a difference in the amount of colchicine to be used, either one is effective. CONCLUSION: In cases of periodic symptoms or cases called periodic fever, exclusion diagnosis is carried out, there is a need to suspect FMF, determine the effect of colchicine, and perform genetic analysis.

Visual projection neurons in the Drosophila lobula link feature detection to distinct behavioral programs.

Visual projection neurons (VPNs) provide an anatomical connection between early visual processing and higher brain regions. Here we characterize lobula columnar (LC) cells, a class of Drosophila VPNs that project to distinct central brain structures called optic glomeruli. We anatomically describe 22 different LC types and show that, for several types, optogenetic activation in freely moving flies evokes specific behaviors. The activation phenotypes of two LC types closely resemble natural avoidance behaviors triggered by a visual loom. In vivo two-photon calcium imaging reveals that these LC types respond to looming stimuli, while another type does not, but instead responds to the motion of a small object. Activation of LC neurons on only one side of the brain can result in attractive or aversive turning behaviors depending on the cell type. Our results indicate that LC neurons convey information on the presence and location of visual features relevant for specific behaviors.

IgG4-related Kidney Disease in Which the Urinalysis, Kidney Function and Imaging Findings Were Normal.

IgG4-related kidney disease (IgG4RKD) is recognized as a fibroinflammatory disease characterized by storiform fibrosis, lymphoplasmacytic infiltration and a high serum IgG4 level. A renal biopsy is necessary to diagnose IgG4RKD in patients without any lesions in other organs. Nephrologists typically perform renal biopsies in patients with abnormal urinalysis, such as proteinuria or hematuria, or renal failure. However, we experienced a patient with IgG4RKD without abnormalities in the urinalysis, renal function or imaging, who had severe interstitial lesions. We therefore propose that renal biopsies should be considered if patients do not show abnormal urinalysis findings and are suspected to have IgG4RKD.

[Marked efficacy of metronidazole for the intestinal pseudoobstruction associated with systemic sclerosis].

In May 2009, a 57-year-old woman who had rheumatoid arthritis since 9 years was admitted to our hospital for dyspnea due to interstitial pneumonia (IP). On admission, she exhibited proximal scleroderma, finger edema, Raynaud's phenomenon, digital pitting scars, ankyloglossia, and esophageal dysmotility. The patient was diagnosed as having systemic sclerosis (SSc), according to the American College of Rheumatology criteria. After initiation of high-dose corticosteroid therapy, gradual amelioration of IP was observed. However, the patient complained of abdominal fullness. Computed tomography and intestine series findings revealed significant dilatation of the small intestine due to intra-abdominal free air and pneumatosis cystoides intestinalis but no mechanical obstruction, leading to a diagnosis of SSc with pseudo-obstruction. The patient underwent decompression with a long intestinal tube, which led to improvement in her symptoms. Although erythromycin (EM) and some prokinetic agents were administered, abdominal involvement recurred several days after resumption of oral ingestion. Therefore, we changed the antibiotic from EM to metronidazole (750 mg/day). Her manifestations were promptly ameliorated by metronidazole therapy in 4 days and did not recur. Metronidazole is an antibiotic used to treat intra-abdominal anaerobic bacterial infections and is also commonly used in preoperative treatment for colorectal surgery. In conclusion, we report a case where SSc-associated pseudo-obstruction was successfully managed by metronidazole therapy.

[Tuberculous peritonitis during etanercept therapy for rheumatoid arthritis].

In August 2010, a 73-year-old woman with rheumatoid arthritis receiving etanercept (ETN) therapy for two years, developed high-fever and abdominal fullness. Though she had not been exposed to tuberculosis, isoniazid prophylaxis was administrated. Antibiotics were not effective. CT images revealed the massive ascites and peritonitis, and Ga scintigraphy demonstrated notable uptake in the peritoneum. Ascites analysis showed an elevated adenosine deaminase activity value (104.9 IU/l) without malignant cells. Moreover, PCR and culture for Mycobacterium tuberculosis were positive. Finally, a diagnosis of tuberculous peritonitis was established. After initiating a standard anti-tuberculosis regimen with four drugs, her clinical condition ameliorated and ascites promptly regressed. Although the tuberculous peritonitis during ETN therapy is rare, this report emphasized the importance of initial suspicion of tuberculosis in these patients with tumor necrosis factor inhibitors such as ETN.

[Cutaneous necrotizing vasculitis in a patient with Behcet's disease; mimicking polyarteritis nodosa].

A 25-year-old-man was referred with an approximately 1-year history of recurrent fever, tonsillitis, testicular pain and testicular swelling in June 2009. He also complained of visual disturbance, some erythema nodosum (EN) like lesions on his lower extremities and oral aphthous ulcerations for 5 months. Opthalmological consultation confirmed retinochoroiditis, and ultrasonography revealed epididymitis. A biopsy of the EN like lesion showed a necrotizing vasculitis of the small and medium-sized vessels with septal panniculitis in the subcutis. The laboratory findings revealed an elevation of CRP and positive HLA-B51. He was diagnosed with incomplete Behcet's disease according to the Japanese criteria (1987). After the initiation of the therapy with 10 mg/day of prednisolone, his symptoms promptly ameliorated. In our case, although epididymitis as well as the histopathological findings suggested polyarteritis nodosa (PN), a diagnosis of BD was established on the basis of other contemporaneous findings. Necrotizing vasculitis as a cutaneous manifestation in patients with BD has been rarely reported. However, BD and PN, including cutaneous PN, have rarely described in conjunction. Therefore, we propose that PN-like necrotizing vasculitis might be the subtype of BD.

Case of refractory otitis media with high-titer positive serum MPO-ANCA value.

A 56-year-old-woman presented a local otolaryngologist with a complaint of hearing loss. She was treated with antibiotics as acute otitis media, however her symptom did not improved. She admitted to our hospital because of hearing loss on both sides, fever, otorrhea and vertigo. On admission, an audiogram showed bilateral mixed conductive-sensorineural hearing loss, and CT image revealed the exudates in bilateral middle ear cavities and mastoid air cells. Moreover, serum level of myeloperoxidase anti-neutrophil cytoplasmic autoantibody (MPO-ANCA) elevated (133EU). Although pulmonary, renal and cutaneous involvements were not noted and the histopathological examination of operated specimen taken from otitis media revealed non-specific inflammatory changes, in the absence of any other obvious causes of otitis media, these findings might be associated with positive serum MPO-ANCA value itself. After the initiation of therapy with methylprednisolone and azathioprine, her symptoms and hearing ability ameliorated and both CRP value and the titer of ANCA became normalized. But, after the improvement by the immunosuppressive treatment, MRSA in the otorrhea persisted. This case suggests that otitis media may be one of the symptoms of vasculitis, and some previous cases described otitis media or hearing loss as rare manifestations of vasculitis. It is important to make an early diagnosis for good prognosis of hearing ability, and we have to consider the differential diagnosis including of ANCA-related vasculitis.

Contribution of IL-18 to eosinophilic airway inflammation induced by immunization and challenge with Staphylococcus aureus proteins.

We previously reported that intranasal challenge with ovalbumin (OVA) plus IL-18 induces airway hyperresponsiveness (AHR) and eosinophilic airway inflammation in mice with OVA-specific T(h)1 cells. These two conditions can be prevented by neutralizing anti-IFN-gamma and anti-IL-13 antibodies, respectively. The mice develop AHR and eosinophilic airway inflammation after challenge with OVA plus LPS instead of IL-18 and endogenous IL-18 is known to be involved. In contrast, IL-18 does not facilitate these changes in mice possessing OVA-specific T(h)2 cells. Here, we investigated whether IL-18 is involved in the development of asthma in mice immunized and challenged with bacterial proteins. Upon intranasal exposure to protein A (SpA) derived from Staphylococcus aureus, mice immunized with SpA exhibited AHR and peribronchial eosinophilic inflammation if IFN-gamma or IL-13 were present, respectively. The CD4(+) T cells from draining lymph nodes (DLNs) of the SpA-immunized and -challenged mice produced a robust IFN-gamma and IL-13 in response to immobilized anti-CD3 antibodies. Treatment with neutralizing anti-IL-18 antibodies prevented asthmatic inflammation concomitant with their impaired potential to express IFN-gamma and IL-13. Furthermore, naive mice that received the CD4(+) T cells from DLNs of SpA-immunized mice developed airway inflammation depending upon the presence of IL-18. Immunodeficient mice that received human PBMCs, which had been stimulated with SpA in vitro, developed dense peribronchial accumulation of human CD4(+) T cells upon SpA challenge. Neutralizing anti-human IL-18 antibodies protected against this airway inflammation. These results suggest the importance of IL-18 for the development of asthmatic inflammation associated with airway exposure to bacterial proteins.

In situ hybridization analysis of the expression of futsch, tau, and MESK2 homologues in the brain of the European honeybee (Apis mellifera L.).

BACKGROUND: The importance of visual sense in Hymenopteran social behavior is suggested by the existence of a Hymenopteran insect-specific neural circuit related to visual processing and the fact that worker honeybee brain changes morphologically according to its foraging experience. To analyze molecular and neural bases that underlie the visual abilities of the honeybees, we used a cDNA microarray to search for gene(s) expressed in a neural cell-type preferential manner in a visual center of the honeybee brain, the optic lobes (OLs). METHODOLOGY/PRINCIPAL FINDINGS: Expression analysis of candidate genes using in situ hybridization revealed two genes expressed in a neural cell-type preferential manner in the OLs. One is a homologue of Drosophila futsch, which encodes a microtubule-associated protein and is preferentially expressed in the monopolar cells in the lamina of the OLs. The gene for another microtubule-associated protein, tau, which functionally overlaps with futsch, was also preferentially expressed in the monopolar cells, strongly suggesting the functional importance of these two microtubule-associated proteins in monopolar cells. The other gene encoded a homologue of Misexpression Suppressor of Dominant-negative Kinase Suppressor of Ras 2 (MESK2), which might activate Ras/MAPK-signaling in Drosophila. MESK2 was expressed preferentially in a subclass of neurons located in the ventral region between the lamina and medulla neuropil in the OLs, suggesting that this subclass is a novel OL neuron type characterized by MESK2-expression. These three genes exhibited similar expression patterns in the worker, drone, and queen brains, suggesting that they function similarly irrespective of the honeybee sex or caste. CONCLUSIONS: Here we identified genes that are expressed in a monopolar cell (Amfutsch and Amtau) or ventral medulla-preferential manner (AmMESK2) in insect OLs. These genes may aid in visualizing neurites of monopolar cells and ventral medulla cells, as well as in analyzing the function of these neurons.

Administration of IL-33 induces airway hyperresponsiveness and goblet cell hyperplasia in the lungs in the absence of adaptive immune system.

Systemic administration of IL-18 induces polyclonal IgE responses by causing NKT cells to express CD40 ligand and to produce IL-4. Administration of IL-33 also induces IgE response, although the mechanism underlying IgE response is unclear. Here, we compared the effects of IL-18 and IL-33 on bone marrow-derived mast cells and basophils as well as non-polarized and T(h)2-polarized CD4(+) T cells in vitro. Basophils, comprising IL-18Ralpha(+) cells (14.2%) and IL-33Ralpha(+) cells (34.6%), and mast cells, comprising IL-18Ralpha(+) cells (2.0%) and IL-33Ralpha(+) cells (95.6%), produce IL-4, IL-6, IL-13, granulocyte macrophage colony-stimulating factor (GM-CSF) and chemokines (RANTES, MIP-1alpha, MIP-1beta and MCP-1), upon stimulation with IL-18 and/or IL-33 in the presence of IL-3. Only basophils strongly produce IL-4. Furthermore, compared with mast cells, basophils produce larger amounts of the above cytokines and chemokines in response to IL-33. Level of IL-33Rbeta-mRNA expression in basophils is higher than that in mast cells. Effect of IL-33 is dependent on ST2 binding, and its signal is transduced via MyD88 in vitro. We also found that IL-2 plus IL-18 or IL-33 alone stimulates non-polarized or T(h)2-polarized CD4(+) T cells to produce IL-4 and IL-13 or IL-5 and IL-13, respectively. We finally showed that administration of IL-33 into mice ST2/MyD88 dependently induces airway hyperresponsiveness (AHR) and goblet cell hyperplasia by induction of IL-4, IL-5 and IL-13 in the lungs. Furthermore, same treatment of RAG-2(-/-) mice, lacking T and B cells, more strikingly induced AHR with marked goblet cell hyperplasia and eosinophilic infiltration in the lungs. Thus, IL-33 induces asthma-like symptom entirely independent of acquired immune system.