GABA Administration Ameliorates Sjogren’s Syndrome in Two Different Mouse Models

Sjögren’s syndrome (SS) is a chronic autoimmune disease characterized by lymphocytic infiltrates in the salivary and lachrymal glands resulting in oral and ocular dryness. There are no clinically approved therapies to slow the progression of SS. Immune cells possess receptors for the neurotransmitter GABA (GABA-Rs) and their activation has immunoregulatory actions. We tested whether GABA administration has potential for amelioration of SS in NOD.B10-H2b and C57BL/6.NOD-Aec1Aec2 mice, two spontaneous SS models. Oral GABA treatment was initiated (1) after the development of sialadenitis but before the onset of overt symptoms, or (2) after the appearance of overt symptoms. When assessed weeks later, GABA-treated mice had greater saliva and tear production, as well as quicker times to salvia flow, in both SS mouse models. This was especially evident when GABA treatment was initiated after the onset of overt disease. This preservation of exocrine function was not accompanied by significant changes in the number or area of lymphocytic foci in the salivary or lachrymal glands of GABA-treated mice and we discuss the possible reasons for these observations. Given that GABA-treatment preserved saliva and tear production which are the most salient symptoms of SS and is safe for consumption, it may provide a new approach to help ameliorate SS.

Case of leprosy mimicking preseptal cellulitis: a diagnostic dilemma

A 36-year-old Asian man presented with swelling over the left frontal region involving the upper eyelids, with associated erythema and tenderness for 1 month duration. Clinically he was diagnosed as a case of preseptal cellulitis, however, the lesion did not improve on broad-spectrum systemic antibiotics. CT showed superficial soft tissue swelling in the forehead extending till the superior part of orbit. Histopathological assessment of the lesion revealed clusters of epithelioid cells with multinucleate giant cells in the dermis along with perivascular and periadnexal lymphocytic infiltrates, suggestive of leprosy. The patient was started on oral steroids with multidrug therapy, following which the patient showed early resolution of the lesion within 10 days of treatment. Leprosy is endemic in India, leprosy with reactional episodes mimics other inflammatory and infective etiologies making diagnosis difficult. Leprosy should be present in an ophthalmologist’s diagnostic repertoire while dealing with periorbital swellings for early clinical diagnosis and favourable outcomes.

Steatosis, Steatohepatitis and Cancer Immunotherapy: An Intricate Story

Immune checkpoint inhibitors represent one of the most significant recent advances in clinical oncology, since they dramatically improved the prognosis of deadly cancers such as melanomas and lung cancer. Treatment with these drugs may be complicated by the occurrence of clinically-relevant adverse drug reactions, most of which are immune-mediated, such as pneumonitis, colitis, endocrinopathies, nephritis, Stevens Johnson syndrome and toxic epidermal necrolysis. Drug-induced steatosis and steatohepatitis are not included among the typical forms of cancer immunotherapy-induced liver toxicity, which, instead, usually occurs as a panlobular hepatitis with prominent lymphocytic infiltrates. Nonetheless, non-alcoholic fatty liver disease is a risk factor for immunotherapy-induced hepatitis, and steatosis and steatohepatitis are frequently observed in this condition. In the present review we discuss how these pathology findings could be explained in the context of current models suggesting immune-mediated pathogenesis for steatohepatitis. We also review evidence suggesting that in patients with hepatocellular carcinoma, the presence of steatosis or steatohepatitis could predict a poor therapeutic response to these agents. How these findings could fit with immune-mediated mechanisms of these liver diseases will also be discussed.

Haemorrhagic ulcerative duodenitis in a patient with COVID-19 infection: clinical improvement following treatment with budesonide

We present a case of a male patient in his mid-30s with COVID-19-induced lung failure requiring extracorporeal membrane oxygenation, who needed an emergency oesophagogastroduodenoscopy due to major upper gastrointestinal bleeding. Endoscopy exposed severe ulcerative duodenitis with diffuse mucosal bleeding. While CT angiography did not show any signs of ischaemia, histopathology revealed duodenitis with substantial inflammatory cell infiltrates consisting of neutrophils and CD3+ T lymphocytes with equal CD4+/CD8+ distribution. Since the composition of cell infiltrates coincides with changes in inflammatory patterns of the respiratory mucosa from patients with COVID-19 and in COVID-19-associated enterocolitis, and systemic dexamethasone treatment became standard of care in ventilated intensive care unit patients with COVID-19 infection, we initiated an individualised therapeutic attempt to treat the duodenitis with topical enteral budesonide. Follow-up oesophagogastroduodenoscopies within 4 weeks of enteral budesonide administration revealed a full clinical and histological healing of the duodenal mucosa with marked reduction of neutrophilic and lymphocytic infiltrates.To our knowledge, the current report is the first description of enteral budesonide treatment of duodenitis in a patient with COVID-19 infection and warrants further investigation, whether budesonide might constitute a novel therapeutic strategy for the management of COVID-19-related intestinal mucosal damage.

Trichotillomania Masked by Diffuse Alopecia Areata: A Case Report

An 11-year-old girl previously treated for tinea capitis presented a 3-month history of continuous decrease in hair density on the vertex, frontal, and parieto-temporal areas of the scalp. Hair pull test was negative. Trichoscopic findings showed black dots, micro-exclamation point hairs, regrowing vellus hair, and zigzag hairs. Histopathology showed CD3+ peribulbar lymphocytic infiltrates and occasional eosinophils around the anagen hair follicle consistent with a non-scarring alopecia. A diagnosis of diffuse alopecia areata was made. Patient was given methylprednisolone (0.5 mg/kg/day) for 2 weeks and noted marked increase in hair density except on focal areas of the scalp. Patient eventually admitted to occasional hair pulling. Trichoscopy revealed trichoptilosis, V-sign, tulip hairs, and multiple broken hairs of varying length while a second biopsy showed trichomalacia and pigment casts consistent with trichotillomania. In this case, where co-existence of alopecia areata and trichotillomania is considered to be uncommon, trichoscopy proved to be an important tool in differentiating hair disorders with similar presentation. Knowing key features of hair diseases can help elucidate the diagnosis when presented with an atypical case.

Cytological Spectrum of Pulmonary Histoplasmosis Diagnosed by Bronchoalveolar Lavage: 12 Years of Experience in French Guiana

Disseminated histoplasmosis is a major cause of mortality in HIV-infected patients. Rapid and efficient diagnosis of Histoplasma capsulatum is crucial. Cytopathology is available in most hospitals and represents a rapid diagnostic alternative. In this study, we reviewed 12 years of experience to describe the cytology of histoplasmosis diagnosed by bronchoalveolar lavage (BAL) in relation to patient characteristics. BAL-diagnosed pulmonary histoplasmosis concerned 17 patients (14 HIV+). BAL cellularity ranged from 76,000 to 125,000 cells/mL in HIV patients, and 117,000 to 160,000 cells/mL in non-HIV patients. Macrophages predominated in all HIV patients (from 60% to 88%), lymphocytic infiltrates ranged from 5% to 15%, and neutrophils were very heterogeneous (from 2% to 32%). The number of H. capsulatum at hot spots seemed greater in HIV-infected than in immunocompetent patients (9 to 375 vs. 4 to 10) and were inversely proportional to the CD4 counts. Yeasts were both intracellular and extracellular in 85.7% of the HIV patients. This is the most comprehensive series detailing the cytological aspects of BAL in the diagnosis of H. capsulatum, focusing on the number of yeasts and their clustering pattern. The cytological examination of the Gomori-Grocott-stained BAL allows a reliable diagnosis of histoplasmosis.

The KrasG12D;Trp53fl/fl murine model of undifferentiated pleomorphic sarcoma is macrophage dense, lymphocyte poor, and resistant to immune checkpoint blockade

Sarcomas are rare, difficult to treat, mesenchymal lineage tumours that affect children and adults. Immunologically-based therapies have improved outcomes for numerous adult cancers, however, these therapeutic strategies have been minimally effective in sarcoma so far. Clinically relevant, immunologically-competent, and transplantable pre-clinical sarcoma models are essential to advance sarcoma immunology research. Herein we show that Cre-mediated activation of KrasG12D, and deletion of Trp53, in the hindlimb muscles of C57Bl/6 mice results in the highly penetrant, rapid onset undifferentiated pleomorphic sarcomas (UPS), one of the most common human sarcoma subtypes. Cell lines derived from spontaneous UPS tumours can be reproducibly transplanted into the hindlimbs or lungs of naïve, immune competent syngeneic mice. Immunological characterization of both spontaneous and transplanted UPS tumours demonstrates an immunologically-‘quiescent’ microenvironment, characterized by a paucity of lymphocytes, limited spontaneous adaptive immune pathways, and dense macrophage infiltrates. Macrophages are the dominant immune population in both spontaneous and transplanted UPS tumours, although compared to spontaneous tumours, transplanted tumours demonstrate increased spontaneous lymphocytic infiltrates. The growth of transplanted UPS tumours is unaffected by host lymphocyte deficiency, and despite strong expression of PD-1 on tumour infiltrating lymphocytes, tumours are resistant to immunological checkpoint blockade. This spontaneous and transplantable immune competent UPS model will be an important experimental tool in the pre-clinical development and evaluation of novel immunotherapeutic approaches for immunologically cold soft tissue sarcomas.

Skin Tightening With Hyperdilute CaHA: Dilution Practices and Practical Guidance for Clinical Practice

Background Over the past several years, hyperdilute calcium hydroxylapatite (CaHA) has emerged as an effective modality for improving skin quality and managing laxity in the face, arms, hands, neck, décolletage, upper arms, abdomen, buttocks, and upper legs, as well as treating cellulite and striae. While undiluted CaHA is used to provide volume, hyperdilute CaHA is distributed across a much larger surface area in a more superficial plane to stimulate neocollagenesis and elastin formation over time. The absence of lymphocytic infiltrates and predominance of type 1 collagen in the tissue response to CaHA make hyperdilute CaHA a valuable tool for nonsurgical skin tightening. Objectives Provide practical step-by-step guidance on patient selection, dilution practices, and optimal injection technique to facilitate incorporation of the technique into clinical practice. Methods Over the course of 3 regional meetings in the United States, 12 expert physician injectors participated in live webinars as part of a continuing medical education program. Results The practical guidance in this manuscript is based upon the most frequently requested information by audience members and the information considered critical for success by the authors. Conclusions The minimally invasive nature of filler injection results in little down time, making this treatment particularly appealing. The recommendations presented are consistent with previously published consensus guidelines on hyperdilute CaHA but are intended to serve as “how-to” guidance from experience of expert injectors who have successfully treated the face and body.

The study of epidemiological, clinical, histopathological and dermoscopic features of lichen planus

<p class="abstract"><strong>Background:</strong> Lichen planus (LP) is a common papulosquamous condition seen by the dermatologists. It can involve the skin, mucous mebranes, hair and nails. There are many subtypes of LP with various clinical, histopathological and dermoscopic features. In this study we intended to study the epidemiological, clinical, histopathological and dermoscopic features of LP.</p><p class="abstract"><strong>Methods:</strong> A total of 73 patients of LP, above the age of 18 years who qualified the inclusion and exclusion criteria were included in the study. A proforma of epidemiological details was noted, clinical and dermoscopic examination of the lesions were done. The punch biopsy specimens of cutaneous lesions were subjected to histopathological examination and the findings noted.</p><p class="abstract"><strong>Results:</strong> Out of the 73 patients included in the study, 44 were males and 29 females with a ratio of 1.51:1. Classic LP was the commonest type of LP. Wickham’s striae (WS) was the most typical and commonest dermoscopic feature of cutaneous LP except lichen planus pigmentosus. Hyperkeratosis, hypergranulosis, acanthosis, band shaped lymphocytic infiltrate, melanophages, basal cell degeneration and saw tooth shaped rete ridges were the significant histopathological features.</p><p class="abstract"><strong>Conclusions:</strong> LP is more common in young adults and shows a male preponderance. WS is the most important diagnostic feature seen on dermoscopy of all the cutaneous types of LP excluding LPP. Interface dermatitis with a band of lymphocytic infiltrates and dermal melanophages is a notable feature of histopathology of LP.</p>