Calcitonin gene-related peptide (CGRP) and adrenomedullin 2/intermedin (AM2/IMD) play important roles in several pathologies, including cardiovascular disease, migraine and cancer. The efficacy of ...drugs targeting CGRP signalling axis for the treatment of migraine patients is sometimes offset by side effects (e.g. inflammation and microvascular complications, including aberrant neovascularisation in the skin). Recent studies using animal models implicate CGRP in lymphangiogenesis and lymphatic vessel function. However, whether CGRP or AM2/IMD can act directly on lymphatic endothelial cells is unknown. Here, we found that CGRP and AM2/IMD induced p44/42 MAPK phosphorylation in a time- and dose-dependent manner in primary human dermal lymphatic endothelial cells (HDLEC) in vitro, and thus directly affected these cells. These new findings reveal CGRP and AM2/IMD as novel regulators of LEC biology and warrant further investigation of their roles in the context of pathologies associated with lymphatic function in the skin and other organs, and therapies targeting CGRP signalling axis.
•CGRP and AM2 induce p44/42 MAPK phosphorylation in human dermal lymphatic endothelial cells in vitro•CGRP and AM2 act directly on proliferating human dermal lymphatic endothelial cells in vitro•Side effects of drugs targeting CGRP signalling in human skin might be attributed to impact on lymphatic endothelial cells•These observations reveal roles for CGRP and AM2 as novel regulators of human dermal lymphatic endothelial cell biology
Hyperprolactinemia is an endocrinological disorder that might arise from various physiologic or pathologic conditions, as well as from pharmacologic sources. These pharmacologic sources include ...antidepressants, antipsychotics, and dopamine receptor-blocking agents. Amitriptyline is classified as a tricyclic antidepressant. While it is FDA-approved primarily for the treatment of depression, amitriptyline also demonstrates efficacy in managing various other conditions, such as anxiety, post-traumatic stress disorder, insomnia, chronic and neuropathic pain, and migraine prevention. We present a case of a 10-year-old patient with a history of autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and migraine headaches who was incidentally found to have elevated prolactin levels while taking amitriptyline for migraine prophylaxis. While risperidone, an antipsychotic that can be used for ASD management, is commonly known to induce hyperprolactinemia, the association between amitriptyline and elevated prolactin is less frequently described in the literature. This case underscores the necessity for healthcare providers across various specialties to be aware of amitriptyline-induced hyperprolactinemia.
Cisplatin (CP), a platinum based anticancer drug is used as one of the first-line therapy for the treatment of different types of solid tumors. However, CP-induced side effects particularly, ...nephrotoxicity is a major concern. A single nephrotoxic dose (7 mg/kg body weight) of CP was administered in rats with or without, pre and post combined multidoses of epigallocatechin gallate (EGCG) and coenzyme Q10 (CoQ10) (15 and 5 mg/kg body weight respectively). CP administration resulted in marked increase in the nephrotoxic parameters with alterations in the oxidative and nitrosative stress markers. The concentration of inflammatory, as well as apoptotic markers were markedly up-regulated in the kidney of the CP-treated group. Furthermore, CP resulted in histological injury in the renal tissues. Combined antioxidant treatment significantly (p < 0.01) attenuated CP-induced oxidative stress, nitrosative stress, inflammatory and apoptotic parameters. Moreover, an improvement in the histopathological changes confirmed the nephroprotective effect of antioxidant treatment. In conclusion, our study indicates that the combinatorial multidoses of EGCG and CoQ10 ameliorate the cisplatin-mediated pathogenesis by improving renal oxidative/nitrosative status, inflammation and apoptosis and thus can be used as a promising protective agent to increase the efficacy of the drug by minimizing its major side effect i.e. nephrotoxicity.
•Nephroprotective effect of pre and post multiple doses of epigallocatechin gallate and Coenzyme Q10 was evaluated in cisplatin induced toxicity in rats.•Combined antioxidant treatment prevented cisplatin induced oxidative stress mediated inflammation, apoptosis and necrosis in renal tissue.•Epigallocatechin gallate and Coenzyme Q10 is an effective combination of antioxidant in preventing cisplatin induced nephrotoxicity.
Septo-optic dysplasia (SOD) is a rare congenital disorder characterized by optic nerve hypoplasia, brain midline structure anomalies, and hypothalamic-pituitary axis hypoplasia. This case report aims ...to highlight the association between SOD and neurodevelopmental disorders, focusing on attention-deficit/hyperactivity disorder (ADHD) in addition to the well-established link with autism spectrum disorder (ASD). A six-year-old male diagnosed with SOD presented with behavioral concerns, including attention and impulse control issues. A comprehensive psychological evaluation confirmed the diagnosis of ADHD and ruled out ASD. Ophthalmological assessments were integral to understanding the patient's condition. This case underscores the importance of recognizing neurodevelopmental disorders in individuals with SOD, with a particular focus on the less common association with ADHD. The co-occurrence of these conditions underscores the complexity of neurodevelopmental disorders and the need for comprehensive evaluation and management. Collaboration between ophthalmologists and mental health specialists is crucial for addressing the diverse needs of these patients. Early identification and intervention for ADHD are essential for optimal developmental outcomes. This case underscores the necessity for further research to elucidate the relationship between SOD and ADHD, emphasizing the importance of holistic patient care and interdisciplinary collaboration in managing individuals with SOD spectrum conditions.
BACKGROUND:HIV-positive individuals have high incidence of anal high-grade squamous intraepithelial lesions (HSIL) at the squamocolumnar junction (SCJ), which can progress to cancer.1 Focal ...radiofrequency ablation (RFA) treats HSIL, but metachronous recurrence remains high and may be improved with circumferential treatment.
SETTING:The study was performed at a single center.
METHODS:This was a prospective trial of circumferential anal RFA using Barrx™ 60 RFA focal catheters in participants with ≥1 anal SCJ HSIL. The entire SCJ was ablated by RFA. Adverse events (AE), symptoms (including pain), and quality of life were assessed. High-resolution anoscopy assessed recurrences at 3, 6, 9, and 12 months. Lesion site biopsies occurred at month 12. Recurrences were retreated with focal RFA.
RESULTS:Ten male participants (9 HIV+), with a median two HSILs (range 2-8) each, enrolled. Median T-cell count and viral load were 730 cells/mcL and 38 copies/mL. Median duration of RFA treatment was 6.5 (5-13) minutes. Lesion persistence occurred in 4 participants (3 at 3 months, 1 at 6 months). Recurrence at a new site occurred in 1 participant at 3 months. No lesion persisted after retreatment. All participants were HSIL free and completely healed by 12 months. Two device-related mild adverse events occurred in one participant each (thrombosed external hemorrhoid and soft anal scar; both resolved). No serious adverse events (SAEs) occurred.
CONCLUSION:Circumferential anal SCJ RFA produced total HSIL eradication with no more than two treatments. Circumferential RFA appears to be well tolerated with minimal pain and no SAEs in HIV+ participants.
HIV-positive individuals have high incidence of anal high-grade squamous intraepithelial lesions (HSIL) at the squamocolumnar junction (SCJ), which can progress to cancer. Focal radiofrequency ...ablation (RFA) treats HSIL, but metachronous recurrence remains high and may be improved with circumferential treatment.
The study was performed at a single center.
This was a prospective trial of circumferential anal RFA using Barrx 60 RFA focal catheters in participants with ≥1 anal SCJ HSIL. The entire SCJ was ablated by RFA. Adverse events (AEs), symptoms, including pain, and quality of life were assessed. High-resolution anoscopy assessed recurrences at 3, 6, 9, and 12 months. Lesion site biopsies occurred at month 12. Recurrences were retreated with focal RFA.
Ten male participants (9 HIV+), with a median 2 HSILs (range 2-8) each, enrolled. Median T-cell count and viral load were 730 cells/mcL and 38 copies/mL. Median duration of RFA treatment was 6.5 (5-13) minutes. Lesion persistence occurred in 4 participants (3 at 3 months, 1 at 6 months). Recurrence at a new site occurred in 1 participant at 3 months. No lesion persisted after retreatment. All participants were HSIL free and completely healed by 12 months. Two device-related mild AEs occurred in 1 participant each (thrombosed external hemorrhoid and soft anal scar; both resolved). No serious AEs occurred.
Circumferential anal SCJ RFA produced total HSIL eradication with no more than 2 treatments. Circumferential RFA seems to be well tolerated with minimal pain and no serious AEs in HIV+ participants. CLINICALTRIALS.GOV:: NCT02189161.
Neutropenic conditions are prevalent in leukemia patients and are often associated with increased susceptibility to infections. In fact, emergency granulopoiesis (EG), a process regulating neutrophil ...homeostasis in inflammatory conditions and infections, may occur improperly in leukemic conditions, leading to reduced neutrophil counts. Unfortunately, the mechanisms central to dysfunctional EG remain understudied in both leukemia patients and leukemic mouse models. However, despite no direct studies on EG response in leukemia are reported, recently certain transcription factors (TFs) have been found to function at the crossroads of leukemia and EG. In this review, we present an update on TFs that can potentially govern the fate of EG in leukemia. Transcriptional control of Fanconi DNA repair pathway genes is also highlighted, as well as the newly discovered role of Fanconi proteins in innate immune response and EG. Identifying the TFs regulating EG in leukemia and dissecting their underlying mechanisms may facilitate the discovery of therapeutic drugs for the treatment of neutropenia.
Purpose
Radiofrequency ablation (RFA) effectively treats esophageal high-grade dysplasia, but its efficacy in treating anal canal high-grade squamous intraepithelial lesions (HSILs) is ...unsubstantiated. This prospective study assessed the safety and efficacy of applying hemi-circumferential RFA to anal canal HSIL.
Methods
Twenty-one HIV-negative participants with HSIL occupying ≤ half the anal canal circumference were treated with hemi-circumferential anal canal RFA. Participants were assessed every 3 months for 12 months with high-resolution anoscopy; recurrence in the treatment zone was re-treated with focal RFA.
Results
Twenty-one participants with a mean of 1.7 lesions (range 1–4) enrolled and completed the trial. Six (29 %) participants had recurrent HSIL within the treated hemi-circumference within 1 year. Four participants (19 %) had persistence of an index lesion at 3 months. One (2.9 %) index HSIL persisted again at 12 months. No participants had more than two RFA treatments. KM curve-predicted HSIL-free survival within the treatment zone at 1 year was 76 % (95 % CI 52–89 %). Comparing the first 7 and last 14 participants, the predicted 1-year HSIL-free survivals are 43 % (95 % CI 10–73 %) and 93 % (95 % CI 59–99 %), respectively (
p
= 0.008), suggesting a learning curve with the treating physician. Multivariable analysis showed decreased recurrence in the last 14 participants (HR 0.02; 95 % CI 0.001–0.63) while increasing BMI increased recurrence (HR 1.43, 95 % CI 1.01–2.01). No participants had device or procedure-related serious adverse events, anal stricture, or heavy bleeding.
Conclusions
Hemi-circumferential RFA yielded a high rate of anal HSIL eradication in HIV-negative patients at 1 year with minimal adverse events. Lesion persistence was probably related to incomplete initial ablation.
Oxidative stress, a pervasive condition induced by stress has been implicated and recognized to be a prominent feature of various pathological states including cancer and their progression. The ...present study sought to validate the effectiveness of chronic unpredictable stress (CUS) on hepatic and renal toxicity in terms of alterations of various in vivo biochemical parameters, oxidative stress markers and the extent of DNA damage in Swiss albino mice. Animals were randomized into different groups based on their exposure to CUS alone, 7,12-dimethylbenz (a) anthracene (DMBA) alone (topical), DMBA-12-O-tetradecanoylphorbol-13-acetate (TPA) (topical), and exposure to CUS prior to DMBA or DMBA-TPA treatment, and sacrificed after 16 weeks of treatment. Prior exposure to CUS increased the pro-oxidant effect of carcinogen as depicted by significantly compromised levels of antioxidants; superoxide dismutase, catalase, glutathione-S-transferase, glutathione reductase, reduced glutathione in hepatic and renal tissues accompanied by a significant elevation of thiobarbituric acid reactive species (TBARS) as compared to DMBA alone or DMBA-TPA treatments. Loss of structural integrity at the cellular level due to stress-induced oxidative damage was demonstrated by significant increases in the hepatic levels of intracellular marker enzymes such as glutamate oxaloacetate transaminase, glutamate pyruvate transaminase and alkaline phosphatase, and significantly reduced levels of uric acid in kidney tissues. The results of DNA damage studies further positively correlated with all the above biochemical measurements. Thus, exposure to physical or psychological stress may significantly enhance the hepatotoxic and nephrotoxic potential of carcinogens through enhanced oxidative stress even if the treatment is topical.
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