IL-17A Orchestrates Reactive Oxygen Species/HIF1α-Mediated Metabolic Reprogramming in Psoriasis.

Immune cell-derived IL-17A is one of the key pathogenic cytokines in psoriasis, an immunometabolic disorder. Although IL-17A is an established regulator of cutaneous immune cell biology, its functional and metabolic effects on nonimmune cells of the skin, particularly keratinocytes, have not been comprehensively explored. Using multiomics profiling and systems biology-based approaches, we systematically uncover significant roles for IL-17A in the metabolic reprogramming of human primary keratinocytes (HPKs). High-throughput liquid chromatography-tandem mass spectrometry and nuclear magnetic resonance spectroscopy revealed IL-17A-dependent regulation of multiple HPK proteins and metabolites of carbohydrate and lipid metabolism. Systems-level MitoCore modeling using flux-balance analysis identified IL-17A-mediated increases in HPK glycolysis, glutaminolysis, and lipid uptake, which were validated using biochemical cell-based assays and stable isotope-resolved metabolomics. IL-17A treatment triggered downstream mitochondrial reactive oxygen species and HIF1α expression and resultant HPK proliferation, consistent with the observed elevation of these downstream effectors in the epidermis of patients with psoriasis. Pharmacological inhibition of HIF1α or reactive oxygen species reversed IL-17A-mediated glycolysis, glutaminolysis, lipid uptake, and HPK hyperproliferation. These results identify keratinocytes as important target cells of IL-17A and reveal its involvement in multiple downstream metabolic reprogramming pathways in human skin.

Differential Influence of IL-9 and IL-17 on Actin Cytoskeleton Regulates the Migration Potential of Human Keratinocytes.

T cells mediate skin immune surveillance by secreting specific cytokines and regulate numerous functions of keratinocytes, including migration during homeostasis and disease pathogenesis. Keratinocyte migration is mediated mainly by proteolytic cleavage of the extracellular matrix and/or by cytoskeleton reorganization. However, the cross-talk between T cell cytokines and actomyosin machinery of human primary keratinocytes (HPKs), which is required for cytoskeleton reorganization and subsequent migration, remains poorly examined. In this study, we describe that IL-9 profoundly reduced the actin stress fibers, inhibited contractility, and reduced the cortical stiffness of HPKs, which resulted in inhibition of the migration potential of HPKs in an adhesion- and MMP-independent manner. Similarly, IL-9 inhibited the IFN-γ-induced migration of HPKs by inhibiting the actomyosin machinery (actin stress fibers, contractility, and stiffness). IL-17A increased the actin stress fibers, promoted cellular contractility, and increased proteolytic collagen degradation, resulting in increased migration potential of HPKs. However, IL-9 inhibited the IL-17A-mediated HPKs migration. Mechanistically, IL-9 inhibited the IFN-γ- and IL-17A-induced phosphorylation of myosin L chain in HPKs, which is a major regulator of the actomyosin cytoskeleton. Finally, in addition to HPKs, IL-9 inhibited the migration of A-431 cells (epidermoid carcinoma cells) induced either by IFN-γ or IL-17A. In conclusion, our data demonstrate the influence of T cell cytokines in differentially regulating the actomyosin cytoskeleton and migration potential of human keratinocytes, which may have critical roles in skin homeostasis and pathogenesis of inflammatory diseases as well as skin malignancies.

Absolute Ligand Discrimination by Dimeric Signaling Receptors.

Many signaling pathways act through shared components, where different ligand molecules bind the same receptors or activate overlapping sets of response regulators downstream. Nevertheless, different ligands acting through cross-wired pathways often lead to different outcomes in terms of the target cell behavior and function. Although a number of mechanisms have been proposed, it still largely remains unclear how cells can reliably discriminate different molecular ligands under such circumstances. Here we show that signaling via ligand-induced receptor dimerization-a very common motif in cellular signaling-naturally incorporates a mechanism for the discrimination of ligands acting through the same receptor.

A Study Comparing the Efficacy of Monopolar Radiofrequency and Glycolic Acid Peels in Facial Rejuvenation of Aging Skin Using Histopathology and Ultrabiomicroscopic Sonography (UBM) - An Evidence Based Study.

BACKGROUND: Radio frequency (RF) and chemical peels have been used for nonablative skin rejuvenation. Both of these cause collagen remodeling in the dermis and neo-collagen formation resulting in facial rejuvenation. There is limited literature on the evaluation of collagen remodeling by objective methods. OBJECTIVE: To compare the benefits of monopolar radiofrequency and glycolic acid peels in facial rejuvenation with regards to histopathology and Ultrabiomicroscopic sonography (UBM). METHODOLOGY: In this study, forty patients with mild to moderate photoaging received four treatments with 3 weeks interval of monopolar radiofrequency on one side of face and glycolic acid peels in increasing concentrations (NeostrataR) on the other side. Pre and post treatment, 2 mm biopsies were taken from both preauricular areas and Ultrasonography using a 35 MHz probe was done from outer canthus of eye and nasolabial folds from both sides of face. A blinded assessment was done to measure the increase in the grenz zone and dermal thickness. RESULTS: In 35/40 patients there was a significant increase in the grenz zone on histopathology and decrease in subepidermal low-echogenic band (SLEB) on UBM of the nasolabial folds on both sides of the face (p < 0.05). CONCLUSION: Radiofrequency and chemical peels showed equal efficacy in the treatment of facial rejuvenation.

Three rare cases of cutaneous phaeohyphomycosis.

Phaeohyphomycosis is a chronic infectious condition caused by dematiaceous fungi which usually involve the skin and subcutaneous tissue. Subcutaneous phaeohyphomycosis is characterised by papulonodules, verrucous, hyperkeratotic or ulcerated plaques, cysts, abscesses, pyogranuloma, non-healing ulcers or sinuses. In India, commonly associated genera are Exophiala, Phialophora, Cladosporium, Curvularia, Fonsecaea and Alternaria. This condition involves the presence of brown-walled hyphal structures in the dermis and epidermis. Here, we are reporting a rare case series of three patients of phaeohyphomycosis with lesions on finger and dorsum of the hand.

Protein translocation without specific quality control in a computational model of the Tat system.

The twin-arginine translocation (Tat) system transports folded proteins of various sizes across both bacterial and plant thylakoid membranes. The membrane-associated TatA protein is an essential component of the Tat translocon, and a broad distribution of different sized TatA-clusters is observed in bacterial membranes. We assume that the size dynamics of TatA clusters are affected by substrate binding, unbinding, and translocation to associated TatBC clusters, where clusters with bound translocation substrates favour growth and those without associated substrates favour shrinkage. With a stochastic model of substrate binding and cluster dynamics, we numerically determine the TatA cluster size distribution. We include a proportion of targeted but non-translocatable (NT) substrates, with the simplifying hypothesis that the substrate translocatability does not directly affect cluster dynamical rate constants or substrate binding or unbinding rates. This amounts to a translocation model without specific quality control. Nevertheless, NT substrates will remain associated with TatA clusters until unbound and so will affect cluster sizes and translocation rates. We find that the number of larger TatA clusters depends on the NT fraction f. The translocation rate can be optimized by tuning the rate of spontaneous substrate unbinding, [Formula: see text]. We present an analytically solvable three-state model of substrate translocation without cluster size dynamics that follows our computed translocation rates, and that is consistent with in vitro Tat-translocation data in the presence of NT substrates.

Unusual clinical manifestations in a case of Alagille syndrome.

Alagille syndrome, also known as arteriohepatic dysplasia, is a multisystem autosomal dominant disorder characterized by chronic cholestasis due to a paucity of intrahepatic bile ducts, peripheral pulmonary artery stenosis with associated vertebral, ocular, and renal anomalies, and characteristic facies. We report a case of Alagille syndrome in a 3-year-old boy with associated pruritus, follicular keratoses, palmar pits, and keratoderma-like changes over the dorsum of the hands. There have been single isolated case reports of phrynoderma and keratoderma. Palmar pits have not been reported in the literature.

A clinico-epidemiological study of different dermoscopic patterns in hyperpigmented facial lesions in a tertiary care centre.

Introduction: Facial pigmentation is a common presentation of patients attending dermatology out patient department (OPD) and is of great concern to patients. Facial pigmentation may be multifactorial and is only rarely diagnosed accurately by a detailed history and clinical examination. Pigmentary disorders cause psychological distress and negatively impact the quality of life of an individual. Aims and Objectives: (1) To study different dermoscopic patterns in facial melanosis. (2) To estimate the frequency of different dermoscopic patterns. Materials and Methods: Patients with facial hyperpigmentation attending the dermatology OPD were recruited after taking their written consent. A detailed history was taken to collect demographic data. Clinical examination and dermoscopy were done in all patients. Biopsy was done as and when required. Descriptive statistics has been used to describe the quantitative data. Qualitative data were presented as frequency and percentage for clinical and dermoscopic patterns. Results: The study included 100 patients with 15 different facial melanoses. The most common age group affected was 21-40 years in 53 (53%) cases. The female-to-male ratio was 1.63:1. Melasma was reported as the most common cause of facial melanosis constituting 49 (49%) of the total cases. Out of the total melasma cases, epidermal melasma constituted 22 (45%) cases, dermal melasma constituted four (4%) cases and mixed melasma constituted 23 (47%) cases. Other cases included were lichen planus pigmentosus (14; 14%), facial acanthosis nigricans (14; 14%), periorbital hyperpigmentation (7; 7%), post-inflammatory hyperpigmentation (4; 4%), exogenous ochronosis (2; 2%), lentigines (2; 2%), frictional melanosis (2;2%), and one case each of Becker's nevus, nevus of Ota, olanzapine-induced hyperpigmentation, Riehl's melanosis, macular amyloidosis, and tanning. Conclusions: Melasma was reported as the most common cause of facial melanosis. The most common dermoscopic feature was accentuated pseudopigment network. The study is beneficial in understanding the different clinical and dermoscopic patterns of facial melanosis, thus helping the physician to effectively manage the conditions and reduce the need of biopsy. Limitations: (1) A small sample size. (2) Histopathological correlation was not done in all cases.

Patient Perspectives of the Impact of Psoriatic Disease on Quality-of-Life in India: Sub-analysis from the Global Psoriasis and Beyond Survey.

Background: Psoriatic disease (PsD), including plaque psoriasis (PsO) and psoriatic arthritis (PsA), comprises a wide spectrum of manifestations and significantly impacts quality-of-life (QoL). Here, we assessed patients' understanding of PsO and PsA as a systemic disease, its impact on their physical and emotional well-being, and patients' experiences with healthcare professionals for shared treatment decision-making. Materials and Methods: The Global Psoriatic Disease and Beyond Survey was a cross-sectional, qualitative, online survey conducted on patients with moderate-to-severe PsO with/without concomitant PsA. This analysis reports findings from Indian patients. Results: Of the 261 surveyed patients, 27% with PsO reported concomitant PsA, of whom 89% reported PsA severity as moderately or highly active. Overall, 92% had heard the term "PsD," and 90% knew their condition was a systemic disease. Few were aware of PsD manifestations (palmoplantar psoriasis, 49%; nail psoriasis, 43%; axial symptoms, 40%; PsA, 34%) and comorbidities (cardiovascular disease, 33%; obesity, 30%; diabetes, 28%). Eighty-nine percent of patients indicated their skin problems had a "very-large" to "extreme-large" impact on QoL. Ninety-seven percent of patients experienced discrimination and stigmatization from others. Eighty-one percent of patients were not involved in deciding treatment goals. Few (PsO, 6%; PsA, 9%) patients were dissatisfied with current treatment; ≥50% patients reported incomplete relief of skin symptoms (PsO) and joint symptoms (PsA) as the reason for dissatisfaction. Conclusion: Lack of awareness of the manifestations and comorbidities associated with PsD and poor QoL highlights the need for patient education, shared treatment decision-making, and a multidimensional approach to PsD management in India.

Sexually transmitted infections in pregnant women and their partners: A clinico-epidemiological study at a tertiary care center, Mumbai, Maharashtra.

Background: Sexually transmitted infections (STIs) during pregnancy are associated with adverse fetal outcome. They should be aggressively sought and treated. We did an analytical study with the primary aim to know the occurrence of STIs in pregnant women and their spouses. Materials and Methods: An observational cross-sectional analytical study of pregnant women with STIs and their spouses was conducted at a tertiary care hospital. Demographic parameters and medical history were recorded. Clinical examination and necessary investigations were done in pregnant females and their spouses. History about sexual behavior and knowledge of STIs were obtained from the questionnaire. Results: The prevalence of STIs in pregnant women was 2.1% (n = 61) out of 2894 pregnant women who attended our institute during the study period with the highest prevalence of HIV (1.1%), and out of 54 examined spouses, 32 spouses were suffering from STIs. Overall, women had poor awareness, knowledge of STIs, and preventive measures compared to men. A significant association was seen between level of education and awareness about HIV/AIDS and other STIs, both in pregnant women and their spouses. Conclusion: Our study showed an overall low prevalence of STIs among pregnant women but showed higher HIV and syphilis prevalence as compared to national prevalence. The serodiscordancy rate was found to be high in HIV, syphilis, and hepatitis B.

An unusual presentation of perianal Bowen's disease in an immunocompromised patient - Excised and grafted.

Bowen's disease also known as bowenoid keratoses, presents as a clinically persistent, progressive red scaly, or crusted plaque which is due to intraepithelial carcinoma and is potentially malignant. Lesions are typically asymptomatic but may be associated with bleeding. We are reporting perianal Bowen's disease in a 30-year-old married HIV-infected male which is excised and underlying healthy ulcer grafted.

Nailfold capillaroscopy as a prognostic marker for connective tissue diseases: An observational clinico-epidemiological study.

Background Nailfold capillaroscopy (NFC) is useful in the diagnosis and assessment of various connective tissue diseases. In this study, NFC findings were studied in patients of systemic sclerosis (SS), systemic lupus erythematosus (SLE) and dermatomyositis. Aims To study the nailfold capillaroscopic findings in patients with connective tissue disorders, their correlation with disease severity, and changes in findings following treatment or disease progression. Methods This observational prospective time-bound clinico-epidemiological study was conducted in 43 patients over 20 months at Topiwala National Medical College and BYL Nair Ch. Hospital, Mumbai. NFC was performed using the polarising mode of a USB 2.0 video-dermatoscope in all 10 fingernails at 50X and 200X. It was repeated at three follow-up visits to look for changes in findings. Results Among SLE patients, eleven (52.4%) had non-specific NFC patterns and eight (38.1%) had SLE patterns. Among systemic sclerosis patients, eight (42.1%) cases had active and late SS patterns respectively, while one (5.3%) each had SLE, non-specific and early SS patterns. After three follow-ups, 10 out of 11 (90.9%) cases with improvement in NFC also showed clinical improvement; this figure was significantly more than 11 out of 23 (47.8%) cases who had no change in NFC but showed clinical improvement. Two of the three dermatomyositis patients showed a non-specific pattern while one showed a late SS pattern at baseline. Limitations A larger sample size would have yielded results with more validity. Standardisation of the interval between baseline and last follow-up to equal to or more than six months would have yielded results with more accuracy. Conclusion Capillary findings change significantly over time and reflect changes in the clinical status of patients of both SLE and systemic sclerosis, and hence are an important prognostic marker. Rather than an overt change in NFC pattern, reduction or increase in abnormal capillaries is a better predictor of change in disease activity.

Vulvar vestibular papillomatosis: A diagnostic conundrum.

Vulvar vestibular papillomatosis (VP) is considered a normal anatomical variant of the vulva. We present a 19-year-old girl with a history of "small itchy growths" on the vulva for 2 months without any associated discharge. These lesions were causing significant anxiety to the patient. Cutaneous examination revealed multiple, uniformly arranged, skin-colored, monomorphic micropapillae on the inner aspect of the labia minora. Biopsy showed mucosal hyperplasia with papillomatosis and loosely arranged subdermal tissue, no koilocytes were spotted. The diagnosis of vulvar VP was made. We want to highlight this clinical entity as most dermatologists are not familiar with this benign condition and easily confuse it with genital warts. This inexperience may result in unnecessary investigations causing psychological discomfort to the patient. We herein present such a case which brings out the diagnostic dilemma.

Gigantic Melanocytosis - The Dark Enigma.

Gigantic melanocytosis is a rare and peculiar familial disorder of pigmentation. It presents as diffuse hyperpigmentation interspersed by raindrop-like hypopigmented macules predominantly involving the sun-exposed areas and later progressing to involve the photoprotected areas as well. All the cases described in the literature were observed to be commencing in the first year of life and were more common in males. Hereby, we report a 28-year-old female who presented with adult-onset gigantic melanocytosis with no similar familial history.

Vulvar Sarcomatoid Squamous Cell Carcinoma: A Rare Entity.

Vulvar squamous cell carcinoma with sarcomatoid features is an extremely rare histological variant of squamous cell carcinoma with co-existence of both epithelial and mesenchymal features. A 70-year-old woman presented with genital lesions for 4 months with associated burning and pain. Examination revealed well-defined bilaterally symmetrical hyperpigmented plaques on labia majora, fleshy erythematous growth on labia minora. Biopsy from the fleshy mass was suggestive of sarcomatoid malignancy. However, immunohistochemistry was positive for cytokeratin AE1/AE3 and negative for desmin and smooth muscle actin. Biopsy from hyperpigmented plaque was suggestive of Bowens disease. On the basis of histopathology and immunohistochemistry findings, diagnosis of vulvar sarcomatoid squamous cell carcinoma with Bowens disease was made and patient was started on external beam radiation therapy. Sarcomatoid squamous cell carcinoma of vulva is very rare cancer that has an aggressive and fatal course. Diagnosis has traditionally been difficult due to a large ratio of sarcomatous to squamous cell component. Due to its rarity, there are no distinct guidelines to direct therapy and care.

Efficacy and Safety Comparison of Basic Fibroblast Growth Factor-Related Decapeptide 0.1% Solution (bFGFrP) Plus Oral PUVA Combination Therapy with Oral PUVA Monotherapy in the Treatment of Vitiligo.

Background: Phototherapy in its different forms, is mainstay of vitiligo management. Combining treatment modalities like topical calcipotriol (for quicker, more intense repigmentation), Low dose azathioprine with PUVA have proven to be beneficial in management of vitiligo due to different mechanisms of repigmentation and their synergistic effects. Topical bFGF-related decapeptide (bFGFrP) application followed by sun exposure/ UVA phototherapy yields effective repigmentation. bFGFrP has shown to aid the targeted phototherapy in smaller lesions and its combinations with other treatment modalities have been very promising. However, there is paucity of studies on combination treatments; especially oral PUVA along with bFGFrP. This study was aimed at evaluating safety and efficacy of combination of bFGFrP with Oral PUVA in vitiligo (larger body surface area 20% or more). Materials and Methods: Phase IV, randomized, multicentre study (N = 120) in adult patients with stable vitiligo of 6 months treatment period with monthly follow up visits. Psoralen (Tab. Melanocyl) dosage 0.6 mg/kg orally 2 h before exposure to UVA phototherapy. Oral PUVA therapy, initially, at an irradiation dose 4 J/cm2 (PUVA group), followed by increments 0.5 J/cm2 every four sittings if tolerated for twice weekly. Primary end point was improvement in extent of repigmentation (EOR) in target lesion (at least 2 cm × 2 cm in greatest dimension, without leukotrichia), while secondary endpoints were improvement in patient global assessment (PGA) and safety at end of 6 months of treatment period in bFGFrP + oral PUVA combination group and Oral PUVA monotherapy group. Results: End of 6 months, significantly greater EOR >50%) was achieved in 61.8% (34 patients, n = 55) from combination group while 30.2% (16 patients, n = 53) from the oral PUVA monotherapy group (n = 53). Regarding Grade of repigmentation (GOR), complete repigmentation was observed 5.5% (3 patients, n = 55) in combination group whereas no patient showed complete repigmentation in monotherapy group (p ≤ 0.05), PGA showed significant overall improvement in combination group (p ≤ 0.05); 6 patients (10.9%) from combination group Vs one (1.9%) showed complete improvement. During treatment period, there were no reported adverse events. Conclusions: Addition of bFGFrP to oral PUVA therapy resulted in intense and faster induction of repigmentation than oral PUVA monotherapy with favorable safety profile.

Complex regional pain syndrome secondary to leprosy.

INTRODUCTION: Leprosy is a chronic infectious disease caused by Mycobacterium leprae affecting the skin and the nerves. Complex regional pain syndrome (CRPS/Sudeck's dystrophy) is a painful and disabling condition--a triad of autonomic, sensory, and motor symptoms disproportionate to the inciting event (inflammatory, infective, or traumatic nerve damage). CASE: A 20-year-old male presented with continuous pain, aggravated by cold and emotions, loss of fine touch and temperature sensation, redness, swelling, along lateral aspect of left hand and forearm with weakness in the grip of 6 months' duration. There was a 5-year history of sensory loss only over left index finger that he ignored. Examination revealed abnormal sensory and autonomic functions along left radial and median nerve distribution that were confirmed by nerve conduction studies suggestive of mononeuritis multiplex. Radial cutaneous nerve biopsy was suggestive of leprosy. Magnetic resonance imaging and ultrasonography showed no compressive etiology; however, MRI showed involvement of brachial plexus. Antileprosy, anti-inflammatory drugs, and steroids were given in view of neuritis because of lepra reaction with supportive measures of physiotherapy, transcutaneous electrical nerve stimulation, to no avail. A surgical median nerve decompression also failed to relieve the pain. Temporary stellate ganglion block improved the pain scale. Thus, excluding all other causes, the final diagnosis was CRPS secondary to leprosy. There is only one reported case of CRPS with leprosy. CONCLUSION: Leprous neuropathy caused the nerve damage that lead to CRPS type 2. Very rarely leprosy can lead to CRPS. CRPS is a diagnosis of exclusion.

Cheilitis granulomatosa (Miescher granulomatous macrocheilitis) with trisomy 21.

A 30-year-old male with Down syndrome presented to us with diffuse swelling of the lower lip of seven years duration. On examination, there was gross enlargement of his lower-lip with fissuring at places. A histopathological specimen from the lower lip showed non-caseating granulomas. We treated our patient with intralesional triamcinolone acetonide and oral clofazimine. We report this case because of the rare association of cheilitis granulomatosa with Down syndrome.

A non healing ulcer on scalp.

Angiosarcoma is a soft tissue tumour with a dismal prognosis. We present a 74 year old male presenting with a non healing ulcer on the scalp. On histopathology a diagnosis of angiosarcoma was made. An early diagnosis and tumour size play a pivotal role in the survival of the patient.

Bowen's disease on two different unrelated anatomical sites (genitals and nail) in succession in an immunocompromised patient.

Bowen's disease (BD) is a premalignant condition. Its exact etiology is unknown but chronic arsenic and sun exposure, and human papillomavirus infection is known predisposing factors. Pigmented lesions of BD represent 1.7%-5.5% of all BD cases. BD in the nail unit is challenging due to its varied clinical presentations such as fissure, ulceration, warty lesion, paronychia, onychocryptosis, and nail dystrophy. We present the case of a 43-year-old married, immunocompromised male (HIV), with a CD 4 count of 478, on tenofovir, atazanavir boosted with ritonavir regimen, known diabetic presented with multiple asymptomatic discrete, rounded, hyperpigmented verrucous papules on both surfaces of shaft of penis and scrotum and a single, 4 cm × 3 cm, irregular, smooth surfaced, hyperpigmented plaque, on the base of the penis extending to the upper part of the scrotum of 1-year duration with history of multiple unprotected sexual exposures with unknown female partners. Regional lymphadenopathy and systemic complaints were absent. Biopsy from hyperpigmented verrucous papule and hyperpigmented plaque was consistent with verruca vulgaris and pigmented Bowen's disease, respectively. The patient was lost to follow-up. Ten months later, he presented with longitudinal melanonychia with a subungual hyperpigmented mass protruding beyond the distal nail margin near the lateral nail fold of the right middle finger nail with an absent Hutchinson's sign. Longitudinal excisional biopsy of nail lesion was consistent with BD. He was started on 5-fluorouracil 5% for BD of genitals and podophyllin application for verruca vulgaris with remarkable improvement in both the lesions and there is no recurrence of nail lesion after 9 months of excision.