Follicular Becker's nevi: A case series and review of literature.

The follicular variant of Becker's nevus is an under-reported entity. We present the rare occurrence of follicular Becker's nevus in 7 patients, confirmed through dermoscopy and histopathological examination. Dermoscopy shows perifollicular hypopigmentation surrounded by a well-defined net-like pigmentation corresponding clinically to the presence of folliculocentric macules. Histology shows prominent basal and suprabasal melanization surrounding the follicle, corresponding to well-defined net-like pigmentation seen on dermoscopy. However, the melanization does not extend along the entire length of the follicular epithelium leading to perifollicular hypopigmentation on dermoscopy. Though biopsy is confirmatory, it is not usually necessary.

Discovery of a novel and highly selective JAK3 inhibitor as a potent hair growth promoter.

JAK-STAT signalling pathway inhibitors have emerged as promising therapeutic agents for the treatment of hair loss. Among different JAK isoforms, JAK3 has become an ideal target for drug discovery because it only regulates a narrow spectrum of γc cytokines. Here, we report the discovery of MJ04, a novel and highly selective 3-pyrimidinylazaindole based JAK3 inhibitor, as a potential hair growth promoter with an IC50 of 2.03 nM. During in vivo efficacy assays, topical application of MJ04 on DHT-challenged AGA and athymic nude mice resulted in early onset of hair regrowth. Furthermore, MJ04 significantly promoted the growth of human hair follicles under ex-vivo conditions. MJ04 exhibited a reasonably good pharmacokinetic profile and demonstrated a favourable safety profile under in vivo and in vitro conditions. Taken together, we report MJ04 as a highly potent and selective JAK3 inhibitor that exhibits overall properties suitable for topical drug development and advancement to human clinical trials.

Dermoscopy of hypopigmented macules unveiling genetic diagnosis of tuberous sclerosis complex type 2 in an infant presenting with sacral chordoma.

A 2-month-old male with surgically resected sacral chordoma presented with multiple hypopigmented macules showing characteristic patchy, sharply demarcated areas of pigment network on dermoscopy. These dermoscopic findings were suggestive of the ash-leaf macules of tuberous sclerosis over other common hypopigmented macules in neonates. Chordomas presenting in early childhood in the sacral location have been reported as a rare manifestation of tuberous sclerosis complex. The combination of these findings led to a diagnosis of tuberous sclerosis, confirmed with the finding of a heterozygous TSC2 gene deletion; treatment with sirolimus resulted in regression of cardiac rhabdomyomas and hypopigmented macules.

Identification and optimization of pyridine carboxamide-based scaffold as a drug lead for Mycobacterium tuberculosis.

New drugs with novel mechanisms of action are urgently needed to tackle the issue of drug-resistant tuberculosis. Here, we have performed phenotypic screening using the Pathogen Box library obtained from the Medicines for Malaria Venture against Mycobacterium tuberculosis in vitro. We have identified a pyridine carboxamide derivative, MMV687254, as a promising hit. This molecule is specifically active against M. tuberculosis and Mycobacterium bovis Bacillus Calmette-Guérin (M. bovis BCG) but inactive against Enterococcus faecalis, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa, and Escherichia coli pathogens. We demonstrate that MMV687254 inhibits M. tuberculosis growth in liquid cultures in a bacteriostatic manner. Surprisingly, MMV687254 was as active as isoniazid in macrophages and inhibited M. tuberculosis growth in a bactericidal manner. Mechanistic studies revealed that MMV687254 is a prodrug and that its anti-mycobacterial activity requires AmiC-dependent hydrolysis. We further demonstrate that MMV687254 inhibits M. tuberculosis growth in macrophages by inducing autophagy. In the present study, we have also carried out a detailed structure-activity relationship study and identified a promising novel lead candidate. The identified novel series of compounds also showed activity against drug-resistant M. bovis BCG and M. tuberculosis clinical strains. Finally, we demonstrate that in contrast to MMV687254, the lead molecule was able to inhibit M. tuberculosis growth in a chronic mouse model of infection. Taken together, we have identified a novel lead molecule with a dual mechanism of action that can be further optimized to design more potent anti-tubercular agents.

Utility of 18F-FDG PET/CT in Assessment of Disease Extent and Response to Treatment in Xanthoma Disseminatum.

The clinical utility of 18F-FDG PET/CT is being increasingly recognized in histiocytic disorders. We report the case of a 23-y-old woman who presented with slowly progressive, yellowish-brown papules, plaques, and nodules over her face and flexures. Besides the multiple cutaneous lesions, lesions of the brain, stomach, gallbladder, and marrow were additionally revealed by baseline 18F-FDG PET/CT. Skin biopsy and the overall clinical picture were consistent with xanthoma disseminatum. Subsequent PET/CT after cladribine therapy revealed a decrease in the extent and metabolic activity of most lesions, suggestive of a favorable response. This case report highlights the potential role of 18F-FDG PET/CT in the accurate assessment of disease extent and posttreatment response in rare histiocytic disorders.

Nondirected, Site-Selective Arylation of Quinone Imine Ketals Derived from Arylamines: One-Pot Access to meta-Substituted Anilines.

Herein, we develop a metal-free, nondirected, site-selective, one-pot approach to meta-arylation of arylamines. This Brønsted acid-catalyzed, direct C-C bond formation offers a broad substrate scope and scalability and creates the ideal conditions for overriding the conventional site-selectivity to furnish meta-substituted anilines. Additionally, the protocol applies to the meta-allylation of anilines and has been extended to afford late-stage functionalization and synthesis of medicinally privileged arylated diamines and densely functionalized anilines. The control experiments and density functional theory studies provide evidence for the proposed mechanism and selectivity.

Practical Access to meta-Substituted Anilines by Amination of Quinone Imine Ketals Derived from Anisidines: Efficient Synthesis of Anti-Psychotic Drugs.

Reversing the conventional site-selectivity of C-H activation provides efficient retrosynthetic disconnections to otherwise unreactive bonds. Described herein is the Brønsted acid-catalyzed reaction that selectively performs meta-amination of anisidines with aliphatic-, heterocyclic- and aromatic amines in a one-pot procedure. In addition to dramatically simplifying the synthesis of meta-substituted anilines, our approach has the advantage of the scalability and remarkable functional group tolerance, including late-stage functionalization of pharmaceutical compounds and natural products. The control experiments and detailed computational analysis provide insight into the reaction mechanism and the origin of meta-selectivity. The protocol extended to the synthesis of challenging tri-aminated arenes and successfully applied for the efficient synthesis of 5-HT6 receptor antagonists, the anti-psychotic drugs viz.. SB-214111, SB-258510, and specifically, anti-schizophrenic drug SB-271046.

Brønsted-Acid-Catalyzed One-Pot Synthesis of ß,ß-Diaryl Esters: Direct Regioselective Approach to Diverse Arrays of 3-Aryl-1-indanone Cores.

A three-component, solvent-dependent, Brønsted-acid-catalyzed reaction of benzaldehydes, silyl enolates and arene nucleophiles has been developed for the synthesis of potential drug candidate 3-aryl-1-indanones. This reaction features the formation of three C-C bonds, high regioselectivity in a one-pot strategy, broad substrate generality, facile scalability (1.04g), high functional group tolerance and viable substrates. The ß-O-silyl ethers generated in-situ from the Mukaiyama aldol reaction were subjected to acid-catalyzed benzylic arylation with strong as well as weak nucleophiles, and the resultant ß,ß-diaryl esters can undergo a third C-C bond formation with excellent regioselectivity through intramolecular cyclization to afford the indanone products in the same pot. Detailed mechanistic insight leads to a feasible reaction pathway. This transformation opens up a practical and adaptable approach to producing a variety of synthetically valuable transformations and enable the synthesis of medicinally valuable (R)-tolterodine and (+)-indatraline.

2022 AAHA Canine Vaccination Guidelines.

These guidelines are an update and extension of previous AAHA peer-reviewed canine vaccination guidelines published in 2017. Vaccination is a cornerstone of canine preventive healthcare and one of the most cost-effective ways of maintaining a dog's health, longevity, and quality of life. Canine vaccination also serves a public health function by forming a barrier against several zoonotic diseases affecting dogs and humans. Canine vaccines are broadly categorized as containing core and noncore immunizing antigens, with administration recommendations based on assessment of individual patient risk factors. The guidelines include a comprehensive table listing canine core and noncore vaccines and a recommended vaccination and revaccination schedule for each vaccine. The guidelines explain the relevance of different vaccine formulations, including those containing modified-live virus, inactivated, and recombinant immunizing agents. Factors that potentially affect vaccine efficacy are addressed, including the patient's prevaccination immune status and vaccine duration of immunity. Because animal shelters are one of the most challenging environments for prevention and control of infectious diseases, the guidelines also provide recommendations for vaccination of dogs presented at or housed in animal shelters, including the appropriate response to an infectious disease outbreak in the shelter setting. The guidelines explain how practitioners can interpret a patient's serological status, including maternally derived antibody titers, as indicators of immune status and suitability for vaccination. Other topics covered include factors associated with postvaccination adverse events, vaccine storage and handling to preserve product efficacy, interpreting product labeling to ensure proper vaccine use, and using client education and healthcare team training to raise awareness of the importance of vaccinations.

Disease Stability in Segmental and Non-Segmental Vitiligo.

INTRODUCTION: Some therapeutic decisions in vitiligo depend on the likelihood of the disease remaining stable and inactive. AIM: To determine a period of disease stability in vitiligo following which reactivation was unlikely. MATERIALS AND METHODS: This cross-sectional descriptive study was carried out in 200 patients where a detailed clinical history of the disease activity and stability over the course of vitiligo was recorded. RESULTS: There were 167 (83.5%) patients with non-segmental vitiligo and 33 (16.5%) with segmental vitiligo. For every 1-year increase in the duration of the disease, stable and active periods increased by 0.7 and 0.3 years, respectively in non-segmental vitiligo and by 0.9 and 0.1 years in segmental vitiligo (P < 0.01). When segmental vitiligo was stable for at least 2 years, it was five times less likely to re-activate than the disease that was stable for less than 2 years (P = 0.16). However, in non-segmental vitiligo, we found no association between the duration of stability and risk of reactivation. CONCLUSIONS: Segmental vitiligo usually becomes inactive after the disease has been stable for 2 years. Non-segmental vitiligo is prone to reactivation even after prolonged periods of stability.

Knowledge, attitude, and practice towards breast cancer and its screening among women in India: A systematic review.

BACKGROUND: Breast cancer is the most common cancer among women in India causing increased mortality. Lack of awareness leads to detection of breast cancer in advanced stages and is difficult to cure then. OBJECTIVE: A systematic review was conducted to evaluate the knowledge, attitude, and practice of breast cancer and its screening among women in India. METHODOLOGY: Literature search was done on electronic databases including PubMed and Google Scholar. Specific keywords related to breast cancer were used such as breast cancer or breast carcinoma AND awareness or knowledge or attitude or education or practice AND women or females AND India. Searches were limited to articles published in English language in the last 10 years. RESULTS: Fifteen studies were selected with a total of 7545 women between the age of 14 and 75 years. Study population varied from health-care professionals, rural and urban women to general population. Majority of the women were married with illiteracy levels ranging from 5.6% to 42.8%. The knowledge of breast cancer was seen to be 62.99%. Knowledge and attitude toward breast cancer screening were 78.67% and 71.10%, respectively. Most reviewed studies showed a significant association of the knowledge of breast cancer with the education level, marital status, and age of study participants. CONCLUSION: Majority of the population knew about breast cancer and had low percentage for practice of screening methods. Programs on information about breast cancer are required. Women from all populations need to be motivated for positive change toward proper screening, early detection, and treatment of breast cancer.