Gregory D. Scott

Central nervous system inflammation induces muscle atrophy via activation of the hypothalamic–pituitary–adrenal axis

Systemic and CNS-delimited inflammation triggers skeletal muscle catabolism in a manner dependent on glucocorticoid signaling.

Enhanced peripheral visual processing in congenitally deaf humans is supported by multiple brain regions, including primary auditory cortex

Brain reorganization associated with altered sensory experience clarifies the critical role of neuroplasticity in development. An example is enhanced peripheral visual processing associated with congenital deafness, but the neural systems supporting this have not been fully characterized. A gap in our understanding of deafness-enhanced peripheral vision is the contribution of primary auditory cortex. Previous studies of auditory cortex that use anatomical normalization across participants were limited by inter-subject variability of Heschls gyrus. In addition to reorganized auditory cortex (cross-modal plasticity), a second gap in our understanding is the contribution of altered modality-specific cortices (visual intramodal plasticity in this case), as well as supramodal and multisensory cortices, especially when target detection is required across contrasts. Here we address these gaps by comparing fMRI signal change for peripheral vs. perifoveal visual stimulation (11–15° vs. 2–7°) in congenitally deaf and hearing participants in a blocked experimental design with two analytical approaches: a Heschls gyrus region of interest analysis and a whole brain analysis. Our results using individually-defined primary auditory cortex (Heschls gyrus) indicate that fMRI signal change for more peripheral stimuli was greater than perifoveal in deaf but not in hearing participants. Whole-brain analyses revealed differences between deaf and hearing participants for peripheral vs. perifoveal visual processing in extrastriate visual cortex including primary auditory cortex, MT+/V5, superior-temporal auditory, and multisensory and/or supramodal regions, such as posterior parietal cortex (PPC), frontal eye fields, anterior cingulate, and supplementary eye fields. Overall, these data demonstrate the contribution of neuroplasticity in multiple systems including primary auditory cortex, supramodal, and multisensory regions, to altered visual processing in congenitally deaf adults.

Role of parasympathetic nerves and muscarinic receptors in allergy and asthma

Parasympathetic nerves control the symptoms and inflammation of allergic diseases primarily by signaling through peripheral muscarinic receptors. Parasympathetic signaling targets classic effector tissues such as airway smooth muscle and secretory glands and mediates acute symptoms of allergic disease such as airway narrowing and increased mucus secretion. In addition, parasympathetic signaling modulates inflammatory cells and non-neuronal resident cell types such as fibroblasts and smooth muscle contributing to chronic allergic inflammation and tissue remodeling. Importantly, muscarinic antagonists are experiencing a rebirth for the treatment of asthma and may be useful for treating other allergic diseases.

Toll-like Receptor 7 Rapidly Relaxes Human Airways

RATIONALE Toll-like receptors (TLRs) 7 and 8 detect respiratory virus single-stranded RNA and trigger an innate immune response. We recently described rapid TLR7-mediated bronchodilation in guinea pigs. OBJECTIVES To characterize TLR7 expression and TLR7-induced airway relaxation in humans and in eosinophilic airway inflammation in guinea pigs. To evaluate the relaxant effects of other TLRs. METHODS Human airway smooth muscle strips were contracted with methacholine in vitro, and responses to TLR7 and TLR8 agonists were assessed. TLR7-mediated nitric oxide production was measured using a fluorescent indicator, and TLR7 expression was characterized using immunofluorescence. TLR7 signaling was also evaluated in ovalbumin-challenged guinea pigs. MEASUREMENTS AND MAIN RESULTS The TLR7 agonist imiquimod (R837) caused rapid dose-dependent relaxation of methacholine-contracted human airways in vitro. This was blocked by the TLR7 antagonist IRS661 and by inhibiting nitric oxide production but not by inhibiting prostaglandin production. TLR7 activation markedly increased fluorescence of a nitric oxide detector. TLR7 was expressed on airway nerves, but not airway smooth muscle, implicating airway nerves as the source of TLR7-induced nitric oxide production. TLR7-mediated relaxation persisted in inflamed guinea pigs airways in vivo. The TLR8 agonists polyuridylic acid and polyadenylic acid also relaxed human airways, and this was not blocked by the TLR7 antagonist or by blocking nitric oxide or prostaglandin production. No other TLRs relaxed the airways. CONCLUSIONS TLR7 is expressed on airway nerves and mediates relaxation of human and animal airways through nitric oxide production. TLR7-mediated bronchodilation may be a new therapeutic strategy in asthma.

Role of TNF-α in virus-induced airway hyperresponsiveness and neuronal M2 muscarinic receptor dysfunction

BACKGROUND AND PURPOSE Infections with respiratory viruses induce exacerbations of asthma, increase acetylcholine release and potentiate vagally mediated bronchoconstriction by blocking inhibitory M2 muscarinic receptors on parasympathetic neurons. Here we test whether virus‐induced M2 receptor dysfunction and airway hyperresponsiveness are tumour necrosis factor‐alpha (TNF‐α) dependent.

Tissue optical clearing, three-dimensional imaging, and computer morphometry in whole mouse lungs and human airways

In whole adult mouse lung, full identification of airway nerves (or other cellular/subcellular objects) has not been possible due to patchy distribution and micron-scale size. Here we describe a method using tissue clearing to acquire the first complete image of three-dimensional (3D) innervation in the lung. We then created a method to pair analysis of nerve (or any other colabeled epitope) images with identification of 3D tissue compartments and airway morphometry by using fluorescent casting and morphometry software (which we designed and are making available as open-source). We then tested our method to quantify a sparse heterogeneous nerve population by examining visceral pleural nerves. Finally, we demonstrate the utility of our method in human tissue to image full thickness innervation in irregular 3D tissue compartments and to quantify sparse objects (intrinsic airway ganglia). Overall, this method can uniquely pair the advantages of whole tissue imaging and cellular/subcellular fluorescence microscopy.

Quantifying Nerve Architecture in Murine and Human Airways Using Three-Dimensional Computational Mapping

The quantitative histological analysis of airway innervation using tissue sections is challenging because of the sparse and patchy distribution of nerves. Here we demonstrate a method using a computational approach to measure airway nerve architecture that will allow for more complete nerve quantification and the measurement of structural peripheral neuroplasticity in lung development and disease. We demonstrate how our computer analysis outperforms manual scoring in quantifying three-dimensional nerve branchpoints and lengths. In murine lungs, we detected airway epithelial nerves that have not been previously identified because of their patchy distribution, and we quantified their three-dimensional morphology using our computer mapping approach. Furthermore, we show the utility of this approach in bronchoscopic forceps biopsies of human airways, as well as the esophagus, colon, and skin.

New‐onset cutaneous lichen planus following therapy for hepatitis C with ledipasvir‐sofosbuvir

To the Editor, Ledipasvir-sofosbuvir (Harvoni, Gilead Sciences, Foster City, CA, USA) is a recently approved single-tablet oral hepatitis C virus (HCV) treatment that produces profound sustained virologic responses and is generally well tolerated. The impact of ledipasvir-sofosbuvir treatment on lichen planus (LP), an inflammatory mucocutaneous disease associated with HCV, has not been previously described. Here, we report a patient with HCV and a 30-year history of LP limited to the oral mucosa who presented with a 1-month history of widespread cutaneous LP following effective treatment and eradication of HCV with ledipasvir-sofosbuvir. A 55-year-old man presented with a 1-month history of a highly pruritic rash on the chest, axillae, groin and penis. His history was notable for a longstanding history of chronic HCV with recent liver biopsy showing Grade 2 activity and Stage 0 fibrosis. His disease was previously treatment-naïve and 6 months prior, he had begun a 3-month course of ledipasvir-sofosbuvir. His three most recent serum tests showed undetectable HCV RNA, indicating a sustained virologic response. Notably, the patient reported a 30-year history of oral LP that had been mild and well-controlled with occasional use of mild topical steroids. There were no new medications. Physical examination revealed numerous pale purple, flat-topped papules and plaques covered by fine, lacy scale on the trunk and extremities, with accentuation in the flexural areas (Fig. 1). There were subtle lacy, annular plaques on the glans penis, and focally eroded reticular white striae on the bilateral buccal mucosa. Fig. 1. Clinical images. A) Erythematous scaly papules with flexural accentuation. B) Closer examination of axillary lesions.

Normative data for flow cytometry immunophenotyping of benign lymph nodes sampled by surgical biopsy

Aims To create clinically relevant normative flow cytometry data for understudied benign lymph nodes and characterise outliers. Methods Clinical, histological and flow cytometry data were collected and distributions summarised for 380 benign lymph node excisional biopsies. Outliers for kappa:lambda light chain ratio, CD10:CD19 coexpression, CD5:CD19 coexpression, CD4:CD8 ratios and CD7 loss were summarised for histological pattern, concomitant diseases and follow-up course. Results We generated the largest data set of benign lymph node immunophenotypes by an order of magnitude. B and T cell antigen outliers often had background immunosuppression or inflammatory disease but did not subsequently develop lymphoma. Conclusions Diagnostic immunophenotyping data from benign lymph nodes provide normative ranges for clinical use. Outliers raising suspicion for B or T cell lymphoma are not infrequent (26% of benign lymph nodes). Caution is indicated when interpreting outliers in the absence of excisional biopsy or clinical history, particularly in patients with concomitant immunosuppression or inflammatory disease.

Presumed Second Focus of Lung Immunoglobulin G4–Related Disease Found to be Adenocarcinoma

We describe a patient presenting with bilateral radiologically similar lung lesions initially diagnosed as immunoglobulin (Ig) G4-related disease from biopsy of one lesion, but radiographic changes 6 months later prompted biopsy of the second lesion and showed adenocarcinoma. No case of lung IgG4-related disease and a distant lung malignancy has been previously reported. This is notable because lung IgG4-related disease often manifests in multiple thoracic locations but is diagnosed from a representative biopsy specimen.