Differential expression of programmed death 1 (PD-1) on various immune cells and its role in human leprosy.

Leprosy is a chronic bacterial disease caused by Mycobacterium leprae. Leprosy patients have been found to have defects in T cells activation, which is critical to the clearance of the bacilli. Treg cell suppression is mediated by inhibitory cytokines such as IL10, IL-35 and TGF-ß and its frequency is higher in leprosy patients. Activation and overexpression of programmed death 1 (PD-1) receptor is considered to one of the pathways to inhibit T-cell response in human leprosy. In the current study we address the effect of PD-1 on Tregs function and its immuno-suppressive function in leprosy patients. Flow cytometry was used to evaluate the expression of PD-1 and its ligands on various immune cells T cells, B cells, Tregs and monocytes. We observed higher expression of PD-1 on Tregs is associated with lower production of IL-10 in leprosy patients. PD-1 ligands on T cells, B cells, Tregs and monocytes found to be higher in the leprosy patients as compared to healthy controls. Furthermore, in vitro blocking of PD-1 restores the Tregs mediated suppression of Teff and increase secretion of immunosuppressive cytokine IL-10. Moreover, overexpression of PD-1 positively correlates with disease severity as well as Bacteriological Index (BI) among leprosy patients. Collectively, our data suggested that PD-1 overexpression on various immune cells is associated with disease severity in human leprosy. Manipulation and inhibition of PD-1 signaling pathway on Tregs alter and restore the Treg cell suppression activity in leprosy patients.

Procedural dermatology and its unmet need.

Procedural dermatology includes invasive conventional dermatologic surgeries which involve significant use of knife and suture, minimally invasive procedures and device-based procedures. Device-based procedures are the easiest to learn and are less prone to human errors due to automation but can lead to monotony, while conventional surgeries require significant skill, craftsmanship and interest. There has been a recent shift in the approach to procedural dermatology as a therapeutic option with complementary and combination models replacing the conventional hierarchical model in which procedures were last in the step-ladder approach. The demand for both conventional dermatologic surgeries and minimally invasive cosmetic procedures is increasing. Unfortunately, this demand has not been met with adequate supply. Consequently, the number of trained professionals with expertise in these procedures is very limited; they are far outnumbered by unqualified practitioners. A limited number of dermatologic surgeons practicing conventional surgeries has resulted in huge waiting lists for vitiligo surgeries, inappropriate excisions for skin cancers and poor cosmetic outcomes of excisions without proper knowledge of flaps and grafts. Increasingly procedures are being performed by inadequately trained personnel, resulting in complications. There is also an absence of good quality research on the subject of procedural dermatology, which has resulted in a lack of standardisation of various procedures and knowledge about the efficacy of various drug-procedure and procedure-procedure combinations. An increasing variety of gimmicky but costly procedures are being offered to the public without much evidence of efficacy. Individual institutional and broad policy directives are needed to address these issues. Special emphasis is required on formal hands-on procedural dermatology training during residency and beyond it.

Clinical, Biochemical, Genetic, and Therapeutic Profile of Patients with Epidermal Necrolysis: A Descriptive Study.

Background: Epidermal necrolysis (SJS/TEN) is a rare but acute severe drug reaction associated with high morbidity and mortality rates. Aims: To describe the clinical, molecular, biochemical, and therapeutic profile of these patients. Methods: A total of 24 acute SJS/TEN patients were recruited during their hospital stay and detailed clinical history and treatment course recorded. Blood samples collected were subjected to DNA and serum separation for molecular and biochemical analysis. Results: Of 24 patients, 18 (75%) were females and six (25%) were males with six SJS, six SJS-TEN overlap, and 12 TEN cases. The inciting drugs were non-steroidal anti-inflammatory (87.50%; n = 21) followed by antibiotics (66.67%; n = 16), antiepileptics (37.50%; n = 9), and others (37.50%; n = 9). Seventeen patients (77.2%) showed skin eruptions within 7 days after drug intake. Different co-morbidities were observed in 22 (91.6%) and 20 (83.3%) patients showed ocular manifestations. Length of hospital stay ranged from 8 to 55 days, 20 (83.3%) patients were treated with corticosteroids, and four (16.6%) received antimicrobial therapy. Interleukin polymorphisms revealed significantly low frequency of IL-4 in the patients, HLA-A locus typing revealed higher frequency of HLA-A*3301 (20.8%), HLA-A*02 (25%), HLA-A*2402 (14.6%), and sera showed raised levels of granulysin and sFas L in the patients compared to controls. Conclusions: The preliminary study illustrates the clinical, molecular, and biochemical features of acute SJS/TEN and provides a better understanding that helps to improve patient care at an earlier stage. It also highlights the use of corticosteroids and antimicrobial therapy for effective treatment of patients.

Genital ulcer disease: A review.

Genital ulcer disease (GUD) continues to be an important cause of morbidity and mortality worldwide. It is an important risk factor for the acquisition of HIV. GUD is mainly caused by five sexually transmitted infections. Three pathogens most frequently associated with GUD are herpes simplex virus 2 (HSV-2), Treponema pallidum, and Haemophilus ducreyi. Although their prevalence varies among different geographical regions, HSV-2 is the leading cause of this syndrome globally. In recent years, there has been an epidemiological transition of HSV-1 with a growing role of this virus as a causative agent of GUD. GUD may present with unique features depending on the etiological agent that can help clinicians identify the etiology and start treatment. However, owing to atypical presentations and co-infections, an accurate clinical diagnosis is often a challenge without confirmatory laboratory tests. Standard methods used to detect the causative pathogens of GUD have limitations. Molecular methods can provide a more sensitive and rapid microbiological diagnosis, with detection of the pathogen from the clinical sample directly. In situations where no laboratory support is available, the syndromic approach for management should be followed. The current scenario, clinical presentation (typical and atypical), laboratory diagnosis, and management of GUD will be discussed in this review. We searched PubMed literature and Google search engine using the terms "genital ulcer disease," "epidemiology of genital ulcer disease," and "clinical features of genital ulcer disease and atypical presentations" and relevant literature was selected to provide current perspectives of GUD.

Mycoplasma genitalium: A new superbug.

Mycoplasma genitalium (MG) is an emerging sexually transmitted pathogen. It is an important cause of nongonococcal urethritis in men and is associated with cervicitis and pelvic inflammatory disease in women, putting them at risk of infertility. Multiple factors that aid pathogenesis of MG include its ability of adhesion, gliding motility, and intracellular invasion by means of the tip organelle. Through intracellular localization and antigenic variation, MG could result in treatment-resistant chronic infection. There are limited data on the prevalence of MG in Indian patients with urogenital syndromes. Recently, a high prevalence of extra genital infection with MG has been reported. Molecular assays are the major diagnostic techniques of MG infection. Antimicrobial agents such as macrolides, along with fluoroquinolones, are the treatment of choice for MG infections. The issue of drug resistance to azithromycin and fluoroquinolones in MG is rising globally. As molecular tests are becoming available for MG, both for the diagnosis and the detection of antimicrobial resistance, any patient with MG infection should then be tested for antimicrobial resistance. Consideration of MG as a cause of sexually transmitted disease in the Indian population is crucial in diagnostic algorithms and treatment strategies. The purpose of this review is to understand the prevalence of MG in different clinical scenarios, molecular mechanisms of pathogenesis, current status of antimicrobial resistance, and its impact on MG treatment.

Patient perception and satisfaction with a smartphone-based teledermatology service initiated during the COVID-19 pandemic at a tertiary care hospital in North India.

Background Telemedicine is being increasingly used to provide healthcare to patients, particularly during the COVID-19 pandemic. Aims The study aimed to study patient perception and satisfaction with a smartphone-based hybrid teledermatology service initiated during the COVID-19 pandemic. Methods This was a cross-sectional telephonic survey including patients ≥18 years of age who had received a teledermatology consultation. After noting the demographic, clinical and teleconsultation details, patients were administered the Telemedicine Satisfaction Questionnaire and an additional 6-item questionnaire. Patients were also asked to give qualitative feedback and suggestions for improvement using a semi-structured interview guide. Results We interviewed 201 subjects. The most common diagnoses were pemphigus (27, 13.4%), superficial fungal infections (24, 11.8%), psoriasis (22, 10.9%) and dermatitis (21, 10.4%). The overall mean Telemedicine Satisfaction Questionnaire score was 4.20± 0.71. One hundred seventy-one (85.1%) patients responded that they would use teledermatology services again, while 168 (83.6%) reported satisfaction with the quality of services. A majority of the patients were largely satisfied with the various components involved, though some concerns were raised about the care perceived as not at par with physical consultations, difficulty in procuring medicines, lack of confidence in photographic diagnoses and the lack of a personal touch. Patients with urticaria (P=0.020), those who were advised a change in treatment (P=0.029) and those with improvement in their skin disease (P=0.026) were more likely to be satisfied. Limitations Our study was conducted during the COVID-19 pandemic when patient acceptability was likely to be higher. Only follow-up patients were included in the study. Conclusion Patient satisfaction levels were generally high with teledermatology. Addressing lacunae that negatively impact patient perception and satisfaction will help in greater acceptance of teledermatology services.

IL-21 plays an important role in modulating "Th17-Treg" cell axis in leprosy Type 1 reactions.

Leprosy type 1 reaction (T1R) is a cell-mediated inflammatory reaction which involves skin and peripheral nerves in leprosy. Lesions with T1R have higher production of IL-17 cytokine from CD4+ T cells along with lower TGF-ß producing FOXP3+ CD4+ Tregs. IL-21 is an important cytokine that promotes the development and stability of Th17 cells in an autocrine manner. It can play an important role in the pathogenesis of T1R in leprosy. However, the mechanism by which IL-21 influences the pathogenic progress of leprosy T1R remains poorly understood. In the present study, we evaluated the expression of IL-21 cytokine in skin lesions of both non-reactional (NR) and T1R via immuno-histochemistry and quantitative PCR (qPCR). Further, expression of various genes (IL-17A, IL-17F, TGF-ß, FOXP3, RORC and IL-21) was also measured by qPCR in cultured cells. We also analyzed the secretion of various cytokines such as of IL-21, IL-17A/F and TGF-ß in the culture supernatants by ELISA. In addition, differentiation of Th17 and Treg cells were studied in PBMC cultures after stimulation with Mycobacterium leprae sonicated antigens and rIL-21 for 48 hrs and the phenotypes of Th17 and Tregs were determined by flowcytometric analysis. Our results clearly indicate that IL-21+T cells were significantly higher in both peripheral blood and skin lesions of T1R as compared to NR patients. Moreover, we observed that recombinant IL-21 cytokine inhibited TGF-ß producing Treg cells differentiation along with up-regulating Th17 cells under in-vitro conditions. The gene expression of IL-21 was significantly negatively correlated with Treg and positively correlated with Th17 cell markers in T1R patients. Our results suggested that IL-21 promotes T1R mediated inflammation via modulating the balance of Th17 and Treg cell populations.

Chronic ocular sequelae in Stevens-Johnson syndrome: a genetic association study.

Purpose: This study sought to investigate the association of molecular markers with chronic ocular sequelae in Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). Methods: One hundred SJS/TEN patients (200 eyes) with confirmed diagnosis were enrolled between July 2011 and July 2015 from a tertiary eye-care hospital, and their clinical histories were noted. Each eye was scored for severity of manifestation on a scale of 0-5. Peripheral blood samples were collected for DNA followed by screening for interleukin (IL-4, IL-13, IL-4R) polymorphisms, HLA-A locus allele typing, and sera to detect levels of the apoptotic markers granulysin and sFas L. Results: Of the 100 enrolled patients (53 males/47 females; age range: 6-58 years), the incriminating drugs were non-steroidal anti-inflammatory (52%), antibiotics (10%), sulphonamides (8%), anti-epileptics (6%), and unknown (24%). Significant differences in the frequencies of IL-4R polymorphism, HLA-A*3301, HLA-A*02, and HLA-A*2402 alleles, and elevated levels of granulysin and sFas L were observed in patients compared to controls. The ocular complications of conjunctival keratinization (p=0.004) showed an association with IL-13 promoter region (IL-13a) genotypes. Conclusions: The study highlights the possible association of interleukin-13 with severity-graded chronic sequelae and the role of HLA-A alleles- HLA-A*3301, HLA-A*02, and HLA-A*2402 in SJS/TEN causation and manifestation. Screening of these alleles may help caregivers to identify markers associated with severe and lifelong ocular complications, and help in appropriate treatment and management of the condition.

Role of diffusion tensor imaging in the evaluation of ulnar nerve involvement in leprosy.

OBJECTIVE: Early detection of peripheral neuropathy is extremely important as leprosy is one of the treatable causes of peripheral neuropathy. The study was undertaken to assess the role of diffusion tensor imaging (DTI) in ulnar neuropathy in leprosy patients. METHODS: This was a case-control study including 38 patients (72 nerves) and 5 controls (10 nerves) done between January 2017 and June 2019. Skin biopsy proven cases of leprosy, having symptoms of ulnar neuropathy (proven on nerve conduction study) were included. MRI was performed on a 3 T MR system. Mean cross-sectional area, fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values of ulnar nerve at cubital tunnel were calculated. Additional ancillary findings and appearance of base sequences were evaluated. RESULTS: Ulnar nerve showed thickening with altered T2W signal in all the affected nerves, having an average cross-sectional area of 0.26 cm2. Low FA with mean of 0.397 ± 0.19 and high ADC with mean of 1.28 ± 0.427 x 10 -3 mm2/s of ulnar nerve in retrocondylar groove was obtained. In the control group, mean cross-sectional area was 0.71cm2 with mean FA and ADC of 0.53 ± 0.088 and 1.03 ± 0.24 x 10 -3 mm2/s respectively. Statistically no significant difference was seen in diseased and control group. Cut-off to detect neuropathy for FA and ADC is 0.4835 and 1.1020 × 10 -3 mm2/s respectively. CONCLUSION: DTI though is challenging in peripheral nerves, however, is proving to be a powerful complementary tool for assessment of peripheral neuropathy. Our study validates its utility in infective neuropathies. ADVANCES IN KNOWLEDGE: 1. DTI is a potential complementary tool for detection of peripheral neuropathies and can be incorporated in standard MR neurography protocol.2. In leprosy-related ulnar neuropathy, altered signal intensity with thickening or abscess of the nerve is appreciated along with locoregional nodes and secondary denervation changes along with reduction of FA and rise in ADC value.3. Best cut-offs obtained in our study for FA and ADC are 0.4835 and 1.1020 × 10 -3 mm2/s respectively.

Vascular neoplasia masquerading as cellulitis and persistent hemorrhagic pericardial effusion.

Tufted angioma and kaposiform hemangioendothelioma are considered to represent two ends of the spectrum of benign vascular neoplasms that predominantly present during infancy or early childhood. We report a rare case of a 5-month-old infant with complicated vascular neoplasm involving the pericardial cavity and skin over cervical region, masquerading as infective pericarditis with cellulitis. The patient responded dramatically to therapy with oral prednisolone and sirolimus, with a significant reduction of size of skin lesions and complete resolution of pericardial effusion over 8 weeks. The report also highlights the importance of a multidisciplinary team in managing such complicated cases.

Mycoplasma hominis: An under recognized pathogen.

Mycoplasma hominis, a commensal of the genital tract, is a potential underestimated pathogen causing both genitourinary and extragenital infections including neonatal infections. Septic arthritis, prosthetic joint infection, central nervous system (CNS) infections, infective endocarditis and abscess formation are common extragenital infections associated mainly with immunocompromised patients. Mycoplasma hominis lipoproteins play an important role in pathogenicity and directly interact with the host immune system. Polymerase chain reaction (PCR) is the mainstay of diagnosis. Increasing resistance to tetracyclines and quinolones which are used for treatment, is a matter of global concern. We reviewed PubMed literature and Google search engine on the recent developments of association of Mycoplasma hominis with various diseases, pathogenesis, diagnosis and treatment.