The high level of functional diversity and plasticity in monocytes/macrophages has been defined within in vitro systems as M1 (classically activated), M2 (alternatively activated) and deactivated ...macrophages, of which the latter two subtypes are associated with suppression of cell mediated immunity, that confers susceptibility to intracellular infection. Although the Leishmania parasite modulates macrophage functions to ensure its survival, what remains an unanswered yet pertinent question is whether these macrophages are deactivated or alternatively activated. This study aimed to characterize the functional plasticity and polarization of monocytes/macrophages and delineate their importance in the immunopathogenesis of Post kala-azar dermal leishmaniasis (PKDL), a chronic dermatosis of human leishmaniasis. Monocytes from PKDL patients showed a decreased expression of TLR-2/4, along with an attenuated generation of reactive oxidative/nitrosative species. At disease presentation, an increased mRNA expression of classical M2 markers CD206, ARG1 and PPARG in monocytes and lesional macrophages indicated M2 polarization of macrophages which was corroborated by increased expression of CD206 and arginase-1. Furthermore, altered vitamin D signaling was a key feature in PKDL, as disease presentation was associated with raised plasma levels of monohydroxylated vitamin D3 and vitamin D3- associated genes, features of M2 polarization. Taken together, in PKDL, monocyte/macrophage subsets appear to be alternatively activated, a phenotype that might sustain disease chronicity. Importantly, repolarization of these monocytes to M1 by antileishmanial drugs suggests that switching from M2 to M1 phenotype might represent a therapeutic opportunity, worthy of future pharmacological consideration.
During infections involving intracellular pathogens, iron performs a double-edged function by providing the pathogen with nutrients, but also boosts the host's antimicrobial arsenal. Although the ...role of iron has been described in visceral leishmaniasis, information regarding its status in the dermal sequel, Post Kala-azar Dermal Leishmaniasis (PKDL) remains limited. Accordingly, this study aimed to establish the status of iron within monocytes/macrophages of PKDL cases.
The intramonocytic labile iron pool (LIP), status of CD163 (hemoglobin-haptoglobin scavenging receptor) and CD71 (transferrin receptor, Tfr) were evaluated within CD14+ monocytes by flow cytometry, and soluble CD163 by ELISA. At the lesional sites, Fe3+ status was evaluated by Prussian blue staining, parasite load by qPCR, while the mRNA expression of Tfr (TfR1/CD71), CD163, divalent metal transporter-1 (DMT-1), Lipocalin-2 (Lcn-2), Heme-oxygenase-1 (HO-1), Ferritin, Natural resistance-associated macrophage protein (NRAMP-1) and Ferroportin (Fpn-1) was evaluated by droplet digital PCR. Circulating monocytes demonstrated elevated levels of CD71, CD163 and soluble CD163, which corroborated with an enhanced lesional mRNA expression of TfR, CD163, DMT1 and Lcn-2. Additionally, the LIP was raised along with an elevated mRNA expression of ferritin and HO-1, as also iron exporters NRAMP-1 and Fpn-1.
In monocytes/macrophages of PKDL cases, enhancement of the iron influx gateways (TfR, CD163, DMT-1 and Lcn-2) possibly accounted for the enhanced LIP. However, enhancement of the iron exporters (NRAMP-1 and Fpn-1) defied the classical Ferritinlow/Ferroportinhigh phenotype of alternatively activated macrophages. The creation of such a pro-parasitic environment suggests incorporation of chemotherapeutic strategies wherein the availability of iron to the parasite can be restricted.
Post-kala-azar-dermal leishmaniasis (PKDL) is an infectious skin disease that occurs as sequela of visceral leishmaniasis (VL) and causes cutaneous lesions on the face and other exposed body parts. ...While the first-line drug miltefosine is typically used for 28 days to treat VL, 12 weeks of therapy is required for PKDL, highlighting the need to evaluate the extent of drug penetration at the dermal site of infection. In this proof-of-concept study, we demonstrate the use of a minimally invasive sampling technique called microdialysis to measure dermal drug exposure in a PKDL patient, providing a tool for the optimization of treatment regimens.
One PKDL patient receiving treatment with miltefosine (50 mg twice daily for 12 weeks) was recruited to this proof-of-concept study and consented to undergo dermal microdialysis. Briefly, a μDialysis Linear Catheter 66 for skin and muscle, a probe with a semi-permeable membrane, was inserted in the dermis. A perfusate (a drug-free physiological solution) was pumped through the probe at a low flow rate, allowing miltefosine present in the dermis to cross the membrane and be collected in the dialysates over time. Protein-free (dialysates) and total (blood and skin biopsies) drug concentrations were analysed using LC-MS/MS.
and conclusions: Using microdialysis, protein-free miltefosine drug concentrations could be detected in the infected dermis over time (Cmax ≈ 450 ng/ml). This clinical proof-of-concept study thus illustrates the potential of dermal microdialysis as a minimally invasive alternative to invasive skin biopsies to quantify drug concentrations directly at the pharmacological site of action in PKDL.
Bio-medical research in COVID-19 times Sil, Amrita; Das, Nilay; Gangopadhyay, Dwijendra
Indian journal of dermatology,
09/2020, Letnik:
65, Številka:
5
Journal Article
Recenzirano
Odprti dostop
The COVID-19 public health emergency has impacted not only the life of the people worldwide but also biomedical and health research in unprecedented ways. The situation has changed dramatically since ...the day WHO declared COVID-19 as “Public Health Emergency of International Concern”1 on 30th January, 2020 and then declared it a “Pandemic” on 11th March, 2020.2,3 Every country has responded to the “Pandemic” differently, and in India the Ministry of Home Affairs introduced the “Disaster Management Act” with suspension on transportations and closure of institutions (including education, training, research, and coaching institutes).4 Challenges have arisen given the social distancing norms, quarantines, limitations in travel, interruption of supply chain and transportation of samples, the chances of research participants and researchers being infected with the virus.
Medical science is evolving constantly and this evolution cannot happen without biomedical research involving human participant. Owing to a tumultuous history, importance of ethical research cannot ...be over emphasized in today's world and the concept of informed consent becomes the guardian of ethics, not only to improve the bonding between the participant and researcher aiding a wholehearted involvement but also ensuring safety for the participants from research related injury/loss. Subject information sheet (SIF) and Informed consent form (ICF) are the fundamental elements of informed consent document. Process of obtaining them from illiterate and vulnerable populations involves the legally authorized representative (LAR) and impartial witness. Audiovisual recording becomes important in case of clinical trials. Process of obtaining informed consent becomes challenging for vulnerable populations as well as during pandemic situations. A comprehensive informed consent is essential for a credible and ethical research.
Background: Elderly population is vulnerable to develop a multitude of dermatological diseases, owing to comorbidities and polypharmacies. Objective: To know the prevalence of dermatological ...conditions in elderly patients attending outpatient department, determine the pattern and relative frequency of skin diseases, and find the relation with associated comorbidities. Materials and Methods: We performed a cross-sectional study on 250 patients, aged ≥60 years. Clinical diagnosis was done, followed by appropriate investigations when required. Descriptive data was analyzed on the parameters of range, mean ± S.D., frequencies, etc., Continuous variables were analyzed using unpaired t-test/Mann-Whitney U test and categorical data by Fisher's exact test/Chi-square test. Statistical software Medcalc version 10.2.0.0 for Windows vista was used. P value =0.05 was considered statistically significant. Results: 250 patients were evaluated, 164 males (65.5%) and 86 females (34.4%). Mean age was 67.87 ± 7.29 years. Commonest disease category was infection (30%), followed by dermatitis (29.6%), papulo-squamous (18.4%), and immunobullous (6.4%). Difference in acute and chronic disease was significant (P = 0.0001). 30% had infections; fungal (50.66%), bacterial (32%), and viral (17.33%). 74 patients had dermatitis (29.6% of study population). Commonest systemic disease was hypertension (23.2%), followed by diabetes mellitus (19.6%). Association of diabetes mellitus was significant (P = 0.0014), more in infective dermatoses (P = 0.0007). All had signs of aging; idiopathic guttate hypomelanosis (51.2%), xerosis (45.2%), seborrheic keratosis (42.6%), cherry angioma (33.2%), senile acne (6.6%). Photoaging was noted as wrinkling (98.8%), freckles (35.6%), purpura (10.8%), telangiectasia (5.6%). People involved in outdoor activity had higher Glogau scale (3.01 ± 0.69) compared to those indoors (2.44 ± 0.74), statistically significant difference (P = 0.001). Conclusion: Our study is the first of its kind, in Eastern India, where we evaluated and explored the disease pattern and extent of geriatric dermatoses among patients attending dermatology OPD of a tertiary care hospital.
Background: Leprosy is a disease having tremendous social implications due to ostracization. Despite continuous efforts made so far to eliminate leprosy, stigma/misbeliefs/adverse attitude toward ...leprosy still prevails among common people. Community perceptions and attitudes towards leprosy patients are critical and unique indicator of how society stereotypes leprosy. Aims: The qualitative study was conducted to explore the perceptions of leprosy patients towards leprosy. Materials and Methods: Two focused group discussions (FGDs) with 19 newly-diagnosed leprosy patients who can speak vernacular were conducted with help of a predetermined FGD-guide between April and June 2019 in the dermatology out-patient department of the tertiary-care center. Both FGD sessions were recorded, transcribed, and translated into English. These verbatims were thematically analyzed and emerging themes were identified with illustrative quotations. Free list and pile sort data obtained were analyzed by Visual Anthropac version 1.0 software for Smith's salience value Cognitive mapping with two-dimensional scaling and hierarchical cluster analysis. Results: Small size of wound, not giving importance, failure to realize, bad luck and scared of being isolated etc., were the most common reported perceptions. Overall, five themes emerged after pile sorting, namely ignorance about the disease, stigma and economic burden, positive perception after diagnosis, treatment-related suggestions, and myths and frequently asked questions. Conclusion: The study concludes that more IEC campaigns are required to abolish the stigma; and ASHA workers/front-line workers can play a pivotal role. The program (NLEP) can also utilize the role of satisfied cured-patient as peer-educator to improve the attitude of society towards this disease.
Introduction: The dynamics of sexually transmitted infections (STIs) are influenced by sexual behaviour (age of first sexual exposure, number of sexual partner/s, sexual orientation, mode of ...intercourse, addiction, occupation, correct and consistent use of condom). The presence of the human immunodeficiency virus (HIV) influences the clinical pattern of STIs and the course of disease too. Objective: Our study was conducted to find the prevalence of STIs among attendees of a designated STI/RTI clinic (DSRC) with the description of clinico-demographic profile and sexual behaviour and association of HIV seropositivity with STIs. Methods: Ours was an institution-based cross-sectional study conducted at DSRC after obtaining ethics committee approval and consent from patients. Clinical diagnosis, demographic profile and sexual history were obtained after maintaining audio-visual privacy. Statistical Analysis: Medcalc, version 10.2 was used. Results: Among 167 patients attending DSRC during the study period, 76 having sexual dysfunctions were excluded. The major STIs diagnosed were primary syphilis (6.59%), secondary syphilis (2.2%), herpes genitalis (42.86%), condyloma acuminata (26.37%), molluscum contagiosum (5.49%), genital candidiasis (7.69%), bowenoid papulosis (3.3%), genital scabies (4.4%) and chancroid (1.1%). Sexual orientations were heterosexual (64.83%), lesbian (1.1%), gay (12.1%), bisexual (17.58%) and with an animal partner (4.4%). Among the total study population, 8.8% was rapid plasma reagin (RPR) reactive and 12.1% was Integrated Counselling and Testing Centre (ICTC) reactive. Among the total patients who used condoms (n = 49), only 15 (16.4% of total participants) used condoms correctly and consistently. Peno-vaginal mode of intercourse (n = 78) was found to be most common followed by oro-insertive (n = 42), oro-receptive (n = 34), ano-insertive (n = 24), ano-receptive (n = 17) and digital insertion (n = 20). Conclusion: Sexual behaviour influences the disease outcome in patients with reproductive tract infection (RTI)/STI.
Background: Impact of COVID-19 pandemic has been immense. An innocent casualty of this disaster is medical education and training. Dermatology, which primarily deals with out-patient services, ...medical and surgical interventions, and in-patient services, was one of the worst hit. The National Medical Commission of India has implemented competency-based medical education (CBME) in Dermatology, Venereology, and Leprosy since 2019. The new curriculum relies on acquiring practical and procedural skills, training skills in research methodology, professionalism, attitude, and communication. Objectives: The study was undertaken to understand the implications of the COVID-19 pandemic on postgraduate dermatology CBME training in India. Materials and Methods: A questionnaire-based survey was carried out on postgraduate dermatology teachers and residents in India after obtaining ethics committee approval. An online semi-structured English questionnaire was administered by Google Forms. The calculated sample size was 366 dermatology faculty and 341 postgraduate students. Validity (Content validity ratio (CVR) ≥0.56) and reliability (Cronbach's alpha coefficient 0.7249) of the questionnaire were determined. Results: Among the 764 responses received, 51.4% reported that their institutes were converted to exclusive COVID hospitals. Domains of dermatology education affected were procedural training (n = 655), bedside clinical teaching (n = 613), outpatient department-based clinical teaching (n = 487), bedside laboratory procedures (n = 463), research activities (n = 453), histopathology (n = 412), and theory classes (n = 302). To keep up with the teaching-learning process, online platforms were mostly utilized: Zoom Meeting (n = 379), Google Meet (n = 287), and WhatsApp Interaction (n = 224). Teaching during ward rounds was significantly more affected in exclusively COVID institutes than non-exclusive COVID institutes (P < 0.001). Psychomotor skill development suffered a major jolt with 26.7% of respondents reporting a standstill (P < 0.001). Communication skills among students suffered due to social distancing, mask, and poor attendance of patients. According to 23.84% of respondents, formative assessment was discontinued. Conclusion: Online seminars, journal clubs, and assessments have been incorporated during the pandemic. Online modalities should be used as a supplementary method as psychomotor skills, communication skills, research work, and bedside clinics may not be replaced by the e-learning.
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