Mycobacterium tuberculosis Sulfolipid-1 Activates Nociceptive Neurons and Induces Cough.

Pulmonary tuberculosis, a disease caused by Mycobacterium tuberculosis (Mtb), manifests with a persistent cough as both a primary symptom and mechanism of transmission. The cough reflex can be triggered by nociceptive neurons innervating the lungs, and some bacteria produce neuron-targeting molecules. However, how pulmonary Mtb infection causes cough remains undefined, and whether Mtb produces a neuron-activating, cough-inducing molecule is unknown. Here, we show that an Mtb organic extract activates nociceptive neurons in vitro and identify the Mtb glycolipid sulfolipid-1 (SL-1) as the nociceptive molecule. Mtb organic extracts from mutants lacking SL-1 synthesis cannot activate neurons in vitro or induce cough in a guinea pig model. Finally, Mtb-infected guinea pigs cough in a manner dependent on SL-1 synthesis. Thus, we demonstrate a heretofore unknown molecular mechanism for cough induction by a virulent human pathogen via its production of a complex lipid.

INVESTIGATING MICROANGIOPATHY USING SWEPT-SOURCE OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY IN PATIENTS WITH SUSAC SYNDROME.

PURPOSE: To determine whether optical coherence tomography angiography is of diagnostic utility for Susac syndrome (SuS) by quantifying microvascular retinal changes. METHODS: We enrolled 18 eyes of 9 healthy controls and 18 eyes of 9 patients with chronic SuS (12 had previous branch retinal artery occlusions and 6 were clinically unaffected). Images of the fovea were taken using an optical coherence tomography angiography system. Analysis included vessel density, fractal dimension, vessel diameter, and measurements of the foveal avascular zone (area, eccentricity, acircularity index, and axis ratio) in deep and superficial retinal layers. RESULTS: Skeleton density and inner ring vessel density were significantly lower in patients with SuS (skeleton density: Susac 0.11 ± 0.01 vs. controls 0.12 ± 0.01, P = 0.027. VD: SuS 0.39 ± 0.04 vs. controls 0.42 ± 0.02, P = 0.041). Eccentricity and axis ratio were significantly higher in patients with SuS (EC: Susac 0.61 ± 0.11, controls 0.51 ± 0.10, P = 0.003; axis ratio: Susac 1.57 ± 0.28, controls 1.39 ± 0.11, P = 0.005). SuS eyes (affected and unaffected) had poorer outcomes of the remaining vascular parameters compared with controls (P > 0.05). CONCLUSION: Optical coherence tomography angiography identified chronic microvascular changes in the eyes of patients with chronic SuS. Even clinically unaffected SuS eyes showed poorer vascular parameters. Although further research is needed, this noninvasive imaging modality seems to have the potential to serve as a valuable additive diagnostic tool.

Quantitative Optical Coherence Tomography Angiography in Patients with Moyamoya Vasculopathy: A Pilot Study.

Moyamoya (MM) disease is a chronic cerebrovascular disease that can lead to progressive stenosis of the terminal portions of the internal carotid arteries and their proximal branches. We sought to investigate and quantify retinal vascular changes in patients with MM vasculopathy (MMV) using optical coherence tomography angiography (OCTA) compared to healthy controls. Our findings reveal retinal microvascular changes in patients with MMV and highlights the potential of OCTA imaging for the detection of subclinical retinal pathology.

Treatment outcomes of PCR-positive acute retinal necrosis.

BACKGROUND: Acute retinal necrosis (ARN) is a progressive necrotizing retinitis caused by viral infection. Optimal management strategies have not been established for this detrimental disease. Previous literature published suggests that Varicella-zoster virus (VZV) and Herpes simplex virus-1 (HSV1) are the most common promoters of acute retinal necrosis (ARN). AIMS: The purpose of our study was to investigate the viral distribution, demographic, and treatment outcomes of ARN. METHODS: A retrospective chart review evaluated data from PCR-positive ARN patients diagnosed between 2009 and 2018. RESULTS: Analysis of fourteen eyes from 12 patients found CMV and VZV as the commonest causes of ARN. Patients on 1 g of valacyclovir three times a day (V1T) had worse vision between first and final visits (mean difference of 1.25 ± 0.65, n = 2) compared with patients treated with 2 g of valacyclovir three times a day (V2T), or 900 mg twice a day of valganciclovir (V9B) (mean difference of - 0.067 ± 0.13, n = 6, and 0.067 ± 0.067, n = 6, respectively). Both V1T patients developed retinal detachments (RD). Both CMV patients treated with intravitreal triamcinolone developed ARN, elevated IOP, and one developed multiple RD. CONCLUSIONS: Our review found increased incidence of CMV-positive ARN. Patients with zone 1 disease had worse initial visual acuity. Moreover, patients had more favorable outcomes with V2T and V9B compared to V1T. CMV-positive patients clinically worsened after intravitreal steroid injections, further underscoring the value of a PCR diagnosis to tailor the patients' treatment plan accordingly.

Futility considerations in surgical ethics.

The topic of futility has been intensely debated in bioethical discourse. Surgical futility encompasses considerations across a continuum of care, from decision-making during initial triage, to the choice to operate or refrain from operating on the critically ill, to withdrawal of life-supporting care. Determinations over futility may result in discord between providers and patients or their families, who might insist that treatment be provided at all costs to sustain life. In this manuscript, we will explore some of the possible sources for and manifestations of these disputes, and describe approaches by which to resolve them. Part I will briefly address some of the reasons that families ask for life-sustaining measures against medical advice in the surgical setting. These include variable determinations of both the quality of life and the inherent value of life (stemming from religious, cultural, and personal beliefs). Part II will detail some general instances in which physicians and surgeons can override requests to provide futile treatment, namely: instances of resource scarcity, interventions which carry a high probability of harm, and those that carry significant moral distress. To conclude, Part III will provide concrete guidelines for navigating futility, making an argument for individual case-based communication models in surgical decision-making.

Metastatic neuroendocrine tumor masquerading as orbital cysticercosis.

Orbital metastases secondary to neuroendocrine tumors are exceedingly rare. We present a unique case of a 30-year-old female initially presenting with fever, chills, periorbital swelling, and painful proptosis. CT orbits revealed two ovoid-shaped ring-enhancing lesions in the right lateral and superior rectus muscles and clear sinuses, atypical for infectious post-septal cellulitis. Further work-up included serologic analysis, auto-immune panel, and MRI. Further imaging showed pseudocystic orbital lesions mimicking orbital cysticercosis. Additionally, given the bilateral nature of the lesions and patient's country of origin, this parasitic process was highly suspected. A course of albendazole and steroids led to resolution of symptoms. With a presentation at age 30, this is by far the youngest case reported in literature to date.

Long-term outcomes of fornix reconstruction and cicatricial entropion repair in ocular mucous membrane pemphigoid and drug-related secondary pemphigoid.

OBJECTIVE: To investigate the long-term outcomes of fornix reconstruction and cicatricial entropion repair in patients with ocular mucous membrane pemphigoid (MMP) and secondary MMP. METHODS: Retrospective chart review of patients with MMP undergoing either fornix reconstruction (with amniotic membrane or buccal mucosal graft) or Wies cicatricial entropion repair between January 1, 2000, and September 1, 2020. Patients had a positive mucosal biopsy and (or) clinical features of MMP or secondary MMP. The primary outcome was overall success of fornix reconstruction based on fornix depth maintenance at latest follow-up. Secondary outcomes included resolution of trichiasis, visual acuity, and improvement of subjective symptoms. RESULTS: Eight patients (10 eyes) with a diagnosis of MMP (3 males and 5 females; median age, 71 years) and 4 patients (4 eyes) with a diagnosis of secondary MMP (2 females and 2 male; median age, 87 years) were enrolled. Mean follow-up was 22.7 months (range, 0.3-87.5 months) for MMP patients and 15.4 months (range, 3.0-43.9 months) for secondary MMP patients. For MMP eyes, 30.0% underwent fornix reconstruction, 60.0% underwent entropion repair, and 10.0% received both. Re-formation of symblepharon and loss of fornix depth occurred in all MMP eyes at an average of 6.4 ± 7.0 months postoperatively, and trichiasis recurred in all patients at the last follow-up visit. In secondary MMP patients, 75.0% of the eyes showed recurrence of symblepharon, and 66.7% re-formed trichiasis. Both MMP and secondary MMP patients had short-term symptom improvements. CONCLUSIONS: Fornix reconstruction and cicatricial entropion repair in our cohort of MMP and secondary MMP patients resulted in short-term symptomatic improvement, but recurrence was seen, on average, at 6 months postoperatively.

Safety and efficacy of micropulse transscleral cyclophotocoagulation: 2-year follow-up in a tertiary Canadian centre.

OBJECTIVE: To describe the long-term results of patients undergoing micropulse cyclophotocoagulation (MPCPC). METHODS: Retrospective review of patients undergoing MPCPC with 1 surgeon between July 2016 and January 2017. Data collected included preoperative intraocular pressure (IOP), number of medications, daily acetazolamide use, and whether inferior, superior, or circumferential MPCPC was performed. This was assessed at postoperative week 1 and postoperative months 1, 3, 6, 12, 18, and 24. RESULTS: A total of 49 patients undergoing MPCPC with 2-year follow-up data was included. Ages ranged from 20 to 91 years (mean age, 69 years; 50% female). Following MPCPC, IOP was significantly lower at all points of follow-up (p < 0.05). At 2-year follow-up, the average IOP was 15 mm Hg (35% reduction). Six patients remained on acetazolamide (average daily dose, 333 mg). Average number of medications had decreased to 2.6 (p > 0.05). No significant structural complications occurred, but 53% required repeat MPCPC applications. The most common complication was failure requiring a secondary IOP-lowering surgical procedure. This occurred in 33% of patients. Subsequent glaucoma surgeries included gonioscopy-assisted transluminal trabeculotomy, iStent, Xen glaucoma implant, and Ahmed glaucoma valve. CONCLUSIONS: MPCPC was successful in reducing IOP in conjunction with a nonsignificant reduction in topical glaucoma medications. However, a large proportion of patients required repeat micropulse applications or invasive glaucoma surgery to achieve IOP control. These results suggest that the clinical efficacy of MPCPC may be lower than that reported in the literature.

Assessing the quality of online information on glaucoma procedures.

OBJECTIVE: To investigate the quality of information related to glaucoma procedures found online using 2 different assessment tools. DESIGN: Cross-sectional survey of 100 web sites found via Google search engine. METHODS: The terms "peripheral iridotomy" and "trabeculectomy" along with synonymous keywords were inputted into Google's search engine. The first 50 functional websites for each term were assessed by 2 independent raters using the DISCERN instrument as well as a quality assessment tool by the Journal of the American Medical Association (JAMA). Statistical analysis included an evaluation of intra-rater reproducibility and interclass correlation between the 2 scales. MAIN OUTCOME MEASURES: (i) Quality of web site content based on DISCERN and JAMA scores, (ii) quality of web site based on categorization of web site (iii), intra-rater reproducibility of each scale, and (iv) interclass correlation between the 2 rating scales. RESULTS: Only 22% of the web sites for peripheral iridotomy and 34% of the web sites for trabeculectomy met all the criteria for JAMA's quality assessment. The mean DISCERN scores for peripheral iridotomy and trabeculectomy were 44 and 43.7, respectively, indicating poor quality. For the DISCERN scale, level of agreement between raters for each question ranged from κ = 0.550 (95% confidence interval [CI] 0.700-1.026) to κ = 0.884 (95% CI 0.751-1.017). For the JAMA 4 scale, level of agreement for each question ranged from κ = 0.874 (95% CI 0.734-1.01) to κ = 1.00. CONCLUSION: Our study indicates that information found online for two common ophthalmic procedures is of variable and poor quality. Thus, patients may be receiving misinformation online and better measures need to be implemented to avoid the dissemination of low-quality health information.

Identification of scavenger receptor B1 as the airway microfold cell receptor for Mycobacterium tuberculosis.

Mycobacterium tuberculosis (Mtb) can enter the body through multiple routes, including via specialized transcytotic cells called microfold cells (M cell). However, the mechanistic basis for M cell entry remains undefined. Here, we show that M cell transcytosis depends on the Mtb Type VII secretion machine and its major virulence factor EsxA. We identify scavenger receptor B1 (SR-B1) as an EsxA receptor on airway M cells. SR-B1 is required for Mtb binding to and translocation across M cells in mouse and human tissue. Together, our data demonstrate a previously undescribed role for Mtb EsxA in mucosal invasion and identify SR-B1 as the airway M cell receptor for Mtb.

Optimization and Evaluation of Antiparasitic Benzamidobenzoic Acids as Inhibitors of Kinetoplastid Hexokinase†1.

Kinetoplastid-based infections are neglected diseases that represent a significant human health issue. Chemotherapeutic options are limited due to toxicity, parasite susceptibility, and poor patient compliance. In response, we studied a molecular-target-directed approach involving intervention of hexokinase activity-a pivotal enzyme in parasite metabolism. A benzamidobenzoic acid hit with modest biochemical inhibition of Trypanosoma brucei hexokinase 1 (TbHK1, IC50 =9.1 µm), low mammalian cytotoxicity (IMR90 cells, EC50 >25 µm), and no appreciable activity on whole bloodstream-form (BSF) parasites was optimized to afford a probe with improved TbHK1 potency and, significantly, efficacy against whole BSF parasites (TbHK1, IC50 =0.28 µm; BSF, ED50 =1.9 µm). Compounds in this series also inhibited the hexokinase enzyme from Leishmania major (LmHK1), albeit with less potency than toward TbHK1, suggesting that inhibition of the glycolytic pathway may be a promising opportunity to target multiple disease-causing trypanosomatid protozoa.

Microfold Cells Actively Translocate Mycobacterium tuberculosis to Initiate Infection.

The prevailing paradigm is that tuberculosis infection is initiated when patrolling alveolar macrophages and dendritic cells within the terminal alveolus ingest inhaled Mycobacterium tuberculosis (Mtb). However, definitive data for this model are lacking. Among the epithelial cells of the upper airway, a specialized epithelial cell known as a microfold cell (M cell) overlies various components of mucosa-associated lymphatic tissue. Here, using multiple mouse models, we show that Mtb invades via M cells to initiate infection. Intranasal Mtb infection in mice lacking M cells either genetically or by antibody depletion resulted in reduced invasion and dissemination to draining lymph nodes. M cell-depleted mice infected via aerosol also had delayed dissemination to lymph nodes and reduced mortality. Translocation of Mtb across two M cell transwell models was rapid and transcellular. Thus, M cell translocation is a vital entry mechanism that contributes to the pathogenesis of Mtb.