Intratympanic application of triamcinolone in sudden hearing loss—radiologic anatomy in cone beam CT and its’ correlation to clinical outcome

European Archives of Oto-Rhino-Laryngology - To evaluate temporal bone cone-beam CT in patients with idiopathic sudden sensorineural hearing loss (ISSNHL) being treated with primary and secondary...     

γδ T cells protect against lung fibrosis via IL-22

Inflammation-induced pulmonary fibrosis (PF) leads to irreversible loss of lung function and is a predictor of mortality in numerous lung diseases. Why some subjects with lung inflammation but not others develop PF is unclear. In a mouse model of hypersensitivity pneumonitis that progresses to lung fibrosis upon repeated exposure to the ubiquitous microorganism Bacillus subtilis, γδ T cells expand in the lung and inhibit collagen deposition. We show that a subset of these γδ cells represents the predominant source of the Th17 cytokine IL-22 in this model. Preventing expression of IL-22, either by mutating the aryl hydrocarbon receptor (AhR) or inhibiting AhR signaling, accelerated lung fibrosis. Direct blockade of IL-22 also enhanced collagen deposition in the lung, whereas administration of recombinant IL-22 inhibited lung fibrosis. Moreover, the presence of protective γδ T cells and IL-22 diminished recruitment of CD4⁺ T cells to lung. These data reveal a protective pathway that involves the inhibition of αβ T cells by regulatory IL-22–secreting γδ T cells.Hypersensitivity pneumonitis (HP) is an inflammatory lung disease that results from repeated inhalation of aerosolized antigens (Selman, 2003). The etiologic agents are composed of a wide variety of organic particles (e.g., mammalian and avian proteins, fungi, and bacteria) and certain small-molecular-weight volatile and nonvolatile chemical compounds. The severity of the inflammatory response depends on the nature of the antigen, the quantity and duration of exposure, and host–environment interactions (Selman, 2003). In chronically exposed patients, pulmonary fibrosis (PF) occurs in up to 41% of cases, resulting in irreversible pulmonary dysfunction and right heart failure (Mönkäre and Haahtela, 1987; Bourke et al., 1989; Lalancette et al., 1993; Yoshizawa et al., 1999). Importantly, lung fibrosis is an independent predictor of mortality in these patients, with a 5-yr mortality of 27% and a median survival of 13 yr (Vourlekis et al., 2004). Although PF is associated with numerous diffuse lung diseases, including autoimmune diseases (e.g., rheumatoid arthritis and systemic sclerosis), idiopathic PF, and sarcoidosis, its pathogenesis is poorly understood with few therapeutic options that arrest progression of fibrotic disease (Luzina et al., 2008).γδ T cells are a unique subset of lymphocytes whose function is poorly understood. These cells, however, have been implicated in the regulation of the immune response generated against microbial pathogens and allergens (Born et al., 2007). The location of γδ T cells in the subepithelium of alveolar and nonalveolar regions of the lung (Wands et al., 2005) suggests that these cells play an important role in the immune response directed against inhaled particles such as microbial pathogens (Nanno et al., 2007). We recently reported that Vγ6/Vδ1⁺ γδ T cells isolated from the lung of mice chronically exposed to Bacillus subtilis express IL-17A (Simonian et al., 2009a). In this model of HP, C57BL/6 mice repeatedly treated with B. subtilis by nasal inhalation develop mononuclear infiltrates in the lung and PF that mimics the human disease (Simonian et al., 2006, 2009a; Barrera et al., 2008). Interestingly, large numbers of γδ T cells, nearly all of which are Vγ6/Vδ1⁺, accumulate in the lung in response to B. subtilis and attenuate lung inflammation and fibrosis upon continued exposure to this ubiquitous environmental microorganism (Simonian et al., 2006). In the absence of γδ T cells, TCR-δ^−/− mice treated with B. subtilis have accelerated lung fibrosis but similar levels of IL-17A to those of WT mice as the result of a compensatory increase in IL-17A expression by CD4⁺ T cells. Conversely, IL-22 levels are reduced in TCR-δ^−/− mice (Simonian et al., 2009a), suggesting that IL-22 may be an important mechanism by which Vγ6/Vδ1⁺ γδ T cells attenuate lung inflammation and fibrosis.In this paper, we show that Vγ6/Vδ1⁺ γδ T cells are the predominant cell type in the lung producing IL-22 in response to chronic B. subtilis exposure. In addition, these γδ T cells differentially express IL-17A and IL-22, with IL-22 being expressed by a subset of IL-17F–producing Vγ6/Vδ1⁺ γδ T cells. In the presence of the d allele of the aryl hydrocarbon receptor (AhR), AhR^d/d mice had reduced levels of IL-22 with accelerated collagen deposition in the lung. Administration of intratracheal recombinant mouse IL-22 (rIL-22) to B. subtilis–exposed AhR^d/d and TCR-δ^−/− mice significantly reduced lung inflammation and CD4⁺ T cell recruitment to lung and collagen deposition, suggesting that Vγ6/Vδ1⁺ γδ T cells regulate lung inflammation and fibrosis through IL-22.     

The Effects of Anesthetic Agent and Carrier Gas on Blood Glucose and Tissue Uptake in Mice Undergoing Dynamic FDG-PET Imaging: Sevoflurane and Isoflurane Compared in Air and in Oxygen

PURPOSE: We sought to identify an anesthetic regime that, unlike isoflurane in air, would maintain glucose homeostasis in mice undergoing Positron emission tomography (PET) imaging with 2-deoxy-2-[18F]fluoro-D: -glucose (FDG). MATERIALS AND METHODS: FDG uptake was also measured in normal and tumor tissues. Athymic and Balb/c nude mice were studied. Blood glucose levels were measured before and after 30 min of FDG PET imaging under isoflurane or sevoflurane carried in air or oxygen. FDG uptake was quantified as a percentage of the injected dose and using Patlak analysis yielding Ki values. RESULTS: Blood glucose levels were more stable under sevoflurane than under isoflurane, especially in the athymic nude mice. Under isoflurane, FDG uptake into myocardium was higher than under sevoflurane and was strongly correlated with the intrascan change in blood glucose. CONCLUSION: Sevoflurane should be preferred for physiologic imaging in mice, minimizing changes in glucose and, for FDG PET, reducing signal spillover from the myocardium.     

Biokinetics and dosimetry of 111In-DOTA-NOC-ATE compared with 111In-DTPA-octreotide

Purpose

The biokinetics and dosimetry of ¹¹¹In-DOTA-NOC-ATE (NOCATE), a high-affinity ligand of SSTR-2 and SSTR-5, and ¹¹¹In-DTPA-octreotide (Octreoscan?, OCTREO) were compared in the same patients.

Methods

Seventeen patients (10 men, 7 women; mean age 60?years), referred for an OCTREO scan for imaging of a neuroendocrine tumour (15), thymoma (1) or medullary thyroid carcinoma (1), agreed to undergo a second study with NOCATE. Whole-body anterior–posterior scans were recorded 0.5 (100?% reference scan), 4, 24 and 48?h (17 patients) and 120?h (5 patients) after injection. In 16 patients the OCTREO scan (178?±?15?MBq) was performed 16?±?5?days before the NOCATE scan (108?±?14?MBq) with identical timing; 1 patient had the NOCATE scan before the OCTREO scan. Blood samples were obtained from 14 patients 5?min to 48?h after injection. Activities expressed as percent of the initial (reference) activity in the whole body, lung, kidney, liver, spleen and blood were fitted to biexponential or single exponential functions. Dosimetry was performed using OLINDA/EXM.

Results

Initial whole-body, lung and kidney activities were similar, but retention of NOCATE was higher than that of OCTREO. Liver and spleen uptakes of NOCATE were higher from the start (p?<?0.001) and remained so over time. Whole-body activity showed similar α and β half-lives, but the β fraction of NOCATE was double that of OCTREO. Blood T _1/2β for NOCATE was longer (19 vs. 6?h). As a result, the effective dose of NOCATE (105?μSv/MBq) exceeded that of OCTREO (52?μSv/MBq), and the latter result was similar to the ICRP 106 value of 54?μSv/MBq. Differential activity measurement in blood cells and plasma showed an average of <5?% of NOCATE and OCTREO attached to globular blood components.

Conclusion

NOCATE showed a slower clearance from normal tissues and its effective dose was roughly double that of OCTREO.     

If You Are Not Counted,You Don’t Count: Estimating the Number of African-American Men Who Have Sex with Men in San Francisco Using a Novel Bayesian Approach

African-American men who have sex with men (AA MSM) have been disproportionately infected with and affected by HIV and other STIs in San Francisco and the USA. The true scope and scale of the HIV epidemic in this population has not been quantified, in part because the size of this population remains unknown. We used the successive sampling population size estimation (SS-PSE) method, a new Bayesian approach to population size estimation that incorporates network size data routinely collected in respondent-driven sampling (RDS) studies, to estimate the number of AA MSM in San Francisco. This method was applied to data from a 2009 RDS study of AA MSM. An estimate from a separate study of local AA MSM was used to model the prior distribution of the population size. Two-hundred and fifty-six AA MSM were included in the RDS survey. The estimated population size was 4917 (95 % CI 1267–28,771), using a flat prior estimated 1882 (95 % CI 919–2463) as a lower acceptable bound, and a large prior estimated 6762 (95 % CI 1994–13,863) as an acceptable upper bound. Point estimates from the SS-PSE were consistent with estimates from multiplier methods using external data. The SS-PSE method is easily integrated into RDS studies and therefore provides a simple and appealing tool to rapidly produce estimates of the size of key populations otherwise difficult to reach and enumerate.     

A truncating PET100 variant causing fatal infantile lactic acidosis and isolated cytochrome c oxidase deficiency

Isolated mitochondrial complex IV (cytochrome c oxidase) deficiency is an important cause of mitochondrial disease in children and adults. It is genetically heterogeneous, given that both mtDNA-encoded and nuclear-encoded gene products contribute to structural components and assembly factors. Pathogenic variants within these proteins are associated with clinical variability ranging from isolated organ involvement to multisystem disease presentations. Defects in more than 10 complex IV assembly factors have been described including a recent Lebanese founder mutation in PET100 in patients presenting with Leigh syndrome. We report the clinical and molecular investigation of a patient with a fatal, neonatal-onset isolated complex IV deficiency associated with multiorgan involvement born to consanguineous, first-cousin British Asian parents. Exome sequencing revealed a homozygous truncating variant (c.142C>T, p.(Gln48*)) in the PET100 gene that results in a complete loss of enzyme activity and assembly of the holocomplex. Our report confirms PET100 mutation as an important cause of isolated complex IV deficiency outside of the Lebanese population, extending the phenotypic spectrum associated with abnormalities within this gene.