Mucocutaneous Ulcers Unmasking Severe Systemic Methotrexate Toxicity - A Case-Series and Review of Literature.

Background: Methotrexate is a widely used immunosuppressant with good efficacy and cost-effectiveness. However, one of the drawbacks of methotrexate has been toxicity due to accidental overdose. During the COVID pandemic, there was an alarming increase in the number of patients with methotrexate toxicity which prompted us to do this study. Objective: To evaluate the clinical features and contributing factors in patients presenting with methotrexate toxicity. Materials and Methods: A detailed evaluation of the clinical features, laboratory indices, contributing factors, and outcomes of the patients presenting with methotrexate toxicity was analyzed. Results: A total of 19 cases were seen during the study period. All of the patients had oral mucositis and several developed cutaneous ulcerations. Laboratory abnormalities included cytopenia, transaminitis, and renal impairment. While sixteen patients recovered successfully, three people died as a result of delays in medical assistance. In addition to comorbidities, pandemic-induced restrictions played a major role in patients accidentally overdosing with methotrexate. Conclusion: This study highlights the fact that even low-dose methotrexate taken incorrectly can result in a lethal outcome, which is preventable.

Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: A Fresh Look at an Old Foe.

Background: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are some of the less common cutaneous adverse drug reactions with significant mortality. Objectives: This study was undertaken with the objective of studying the demographics and clinical profile of SJS/TEN and identifying parameters associated with mortality. Materials and Methods: All patients with SJS/TEN over 10 years (2010-2020) were included in the study. Data obtained from in-patient and out-patient records were analysed. Results: A total of 82 patients with SJS/TEN were admitted to our centre over a period of 10 years. Patients with SJS were significantly younger than those with TEN, with a male: female ratio >1 in SJS and <1 in TEN. The most commonly implicated drugs were antiepileptics (n = 29, 35.4%), antibiotics (n = 20, 24.4%). and Non-steroidal antiinflammatory drugs (NSAIDs) (n = 7, 8.5%). The mortality rate in the TEN group was 16% (n = 8). Certain factors such as cutaneous lesions preceding mucosal lesions at onset, high mean Body surface area (BSA) of denudation and a transfer to intensive care unit (ICU) more than 7 days after admission were significantly associated with higher mortality. There was no difference between survivors and deaths in terms of delay in hospitalisation, total disease duration, implicated drug, delay in initiation of therapy, the onset of re-epithelialisation, Severity-of-illness score for TEN (SCORTEN) and total duration of hospital stay. Conclusion: Factors significantly associated with increased mortality in TEN were cutaneous onset of lesions, mean BSA of involvement and transfer to the intensive care unit (ICU) beyond day 7 of admission.

Mucocutaneous manifestations of human immunodeficiency virus (HIV) infection in children in relation to the degree of immunosuppression.

BACKGROUND: Human immunodeficiency virus (HIV) infection in children is becoming a common occurrence. Worldwide, limited studies have been done on the mucocutaneous manifestations in HIV-positive children. The aim of our study was to analyze the spectrum of mucocutaneous manifestations of pediatric HIV infection and correlate to degree of immunosuppression. MATERIAL AND METHODS: One hundred and sixty-five children under 18 years with HIV, who presented to the departments of dermatology and pediatrics, were examined for mucocutaneous manifestations. Patients were classified into four groups of immunodeficiency such as normal, mild, advanced, and severe, based on NACO guidelines of immunosuppression. The most recent CD4 count (within 6 months of study period) was considered. RESULTS: One hundred and sixty-five patients were examined, and skin manifestations were seen in 100 (61%) of them.The highest incidence of mucocutaneous manifestations was in 6-10 age group. Papular pruritic eruptions (PPE) (16%) was the most common condition, with highest prevalence in severe CD4 category (38%). Molluscum contagiosum (MC) (10%) was the most common infectious condition, with highest prevalence in advanced CD4 category (14%). Severe cutaneous adverse reactions (SCAR) caused by nevirapine were seen in three children. The percentage of skin manifestations was highest in the advanced (107%) and severe (100%) CD4 category. There was no significant difference in manifestations between those who were on antiretroviral therapy (ART) and those not. CONCLUSION: The percentage of skin manifestations increased with degree of CD4 depletion. PPE was found to be the hallmark of severe immunosuppression. However, opportunistic infections did not correlate with severity of immunodeficiency.

Structure and Function of Cross-class Complexes of G Protein-coupled Secretin and Angiotensin 1a Receptors.

Complexes of secretin (SecR) and angiotensin 1a (Atr1a) receptors have been proposed to be functionally important in osmoregulation, providing an explanation for overlapping and interdependent functions of hormones that bind and activate different classes of GPCRs. However, the nature of these cross-class complexes has not been well characterized and their signaling properties have not been systematically explored. We now use competitive inhibition of receptor bioluminescence resonance energy transfer and bimolecular fluorescence complementation to establish the dominant functionally important state as a symmetrical homodimeric form of SecR decorated by monomeric Atr1a, interacting through lipid-exposed faces of Atr1a TM1 and TM4. Conditions increasing prevalence of this complex exhibited negative allosteric modulatory impact on secretin-stimulated cAMP responses at SecR. In contrast, activating Atr1a with full agonist in such a complex exhibited a positive allosteric modulatory impact on the same signaling event. This modulation was functionally biased, with secretin-stimulated calcium responses unaffected, whereas angiotensin-stimulated calcium responses through the complex were reduced or absent. Further supporting this interpretation, Atr1a with mutations of lipid-exposed faces of TM1 and TM4 that did not affect its ability to bind or signal, could be expressed in the same cell as SecR, yet not exhibit either the negative or positive allosteric impact on cAMP observed with the inactive or activated states of wild type Atr1a on function, and not interfere with angiotensin-stimulated calcium responses like complexes with Atr1a. This may provide a more selective means of exploring the physiologic functional impact of this cross-class receptor complex without interfering with the function of either component receptor.

Spectrum of pediatric dermatological emergencies at a tertiary care hospital in India: a descriptive study.

BACKGROUND: Dermatological emergencies in children are not uncommon. Worldwide, limited studies have been done to study the spectrum of such emergencies. The aim of our study was to analyze the spectrum of dermatological emergencies in the pediatric age group. MATERIALS AND METHODS: Over a period of 18 months, ninety consecutive patients under 18 years of age presenting with cutaneous in addition to emergency disorders as assessed by the Nelson's severity scoring system were recruited. RESULTS: The most common emergency was primary cutaneous infections (40%), followed by adverse cutaneous drug reactions (13.33%). Staphylococcal scalded skin syndrome was the most frequent infection, and the most common adverse cutaneous drug reaction was Stevens-Johnson syndrome and toxic epidermal necrolysis. Other emergencies included purpura fulminans (12.22%), congenital dermatoses (11.11%), vasculitis (8.90%), angioedema (6.67%), collagen vascular diseases (2.22%), serum sickness (2.22%), post-varicella cerebellitis (1.11%), post-infected scabies glomerulonephritis (1.11%), and Langerhans cell histiocytosis (1.11%). These emergencies presented in equal numbers to the outpatient department of dermatology or pediatrics and to the emergency department. CONCLUSION: Our study recommends the use of standard scoring systems such as the Nelson's score to assess sick children. The appropriateness of this scale or other scales for the assessment of dermatological emergencies needs to be established. Over half of our cases were initially assessed by pediatricians and emergency personnel, highlighting the importance of spreading awareness about cutaneous emergencies and providing them with access to a dermatologist's services.

Molecular basis for binding and subtype selectivity of 1,4-benzodiazepine antagonist ligands of the cholecystokinin receptor.

Allosteric binding pockets in peptide-binding G protein-coupled receptors create opportunities for the development of small molecule drugs with substantial benefits over orthosteric ligands. To gain insights into molecular determinants for this pocket within type 1 and 2 cholecystokinin receptors (CCK1R and CCK2R), we prepared a series of receptor constructs in which six distinct residues in TM2, -3, -6, and -7 were reversed. Two novel iodinated CCK1R- and CCK2R-selective 1,4-benzodiazepine antagonists, differing only in stereochemistry at C3, were used. When all six residues within CCK1R were mutated to corresponding CCK2R residues, benzodiazepine selectivity was reversed, yet peptide binding selectivity was unaffected. Detailed analysis, including observations of gain of function, demonstrated that residues 6.51, 6.52, and 7.39 were most important for binding the CCK1R-selective ligand, whereas residues 2.61 and 7.39 were most important for binding CCK2R-selective ligand, although the effect of substitution of residue 2.61 was likely indirect. Ligand-guided homology modeling was applied to wild type receptors and those reversing benzodiazepine binding selectivity. The models had high predictive power in enriching known receptor-selective ligands from related decoys, indicating a high degree of precision in pocket definition. The benzodiazepines docked in similar poses in both receptors, with C3 urea substituents pointing upward, whereas different stereochemistry at C3 directed the C5 phenyl rings and N1 methyl groups into opposite orientations. The geometry of the binding pockets and specific interactions predicted for ligand docking in these models provide a molecular framework for understanding ligand selectivity at these receptor subtypes. Furthermore, the strong predictive power of these models suggests their usefulness in the discovery of lead compounds and in drug development programs.

Effects of increased response effort and reinforcer delay on choice and aberrant behavior.

A four-phase investigation was completed to analyze the utility of forced-choice preference assessments when response effort and reinforcer delays are altered within a subsequent reinforcer assessment. The results indicated that access to highly preferred stimuli continued to serve as a reinforcer when increased response effort was required. When reinforcer delay was increased, the utility of preferred stimuli to serve as a reinforcer was variable. Despite stimuli continuing to serve as reinforcers for academic task engagement, increased response effort and reinforcer delay resulted in an increased level of aberrant behavior.

Eczema herpeticum in two elderly patients.

Two elderly patients with eczema herpeticum are being reported. The First patient did not respond to the conventional dose of acyclovir. The second case was seen in a patient with air borne contact dermatitis.