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Abstract Background Neuroprotective agents have the potential to improve the outcomes of revascularisation therapies in acute ischemic stroke patients (AIS) and in those unable to receive revascularisation. Afamelanotide, a synthetic α-melanocyte stimulating hormone analogue, is a potential novel neuroprotective agent. We set out to assess the feasibility and safety of afamelanotide for the first time in AIS patients. Methods AIS patients within 24 h of onset, with perfusion abnormality on imaging (Tmax) and otherwise ineligible for revascularisation therapies were enrolled. Afamelanotide 16 mg implants were administered subcutaneously on Day 0 (D0, day of recruitment), D1 and repeated on D7 and D8, if not well recovered. Treatment emergent adverse events (TEAEs) and neurological assessments were recorded regularly up to D42. Magnetic resonance imaging (MRI) with FLAIR sequences were also performed on D3 and D9. Results Six patients (5 women, median age 81, median NIHSS 6) were recruited. Two patients received 4 doses and four patients received 2. One patient (who received 2 doses), suffered a fatal recurrent stroke on D9 due to a known complete acute internal carotid artery occlusion, assessed as unrelated to the study drug. There were no other local or major systemic TEAEs recorded. In all surviving patients, the median NIHSS improved from 6 to 2 on D7. The median Tmax volume on D0 was 23 mL which was reduced to a FLAIR volume of 10 mL on D3 and 4 mL on D9. Conclusions Afamelanotide was well tolerated and safe in our small sample of AIS patients. It also appears to be associated with good recovery and radiological improvement of salvageable tissue which needs to be tested in randomized studies. ClinicalTrials.gov Identifier NCT04962503, First posted 15/07/2021.

Background: Neuroprotective agents have the potential to improve the outcomes of revascularisation therapies in acute ischemic stroke patients (AIS) and in those unable to receive revascularisation. Afamelanotide, a synthetic α-melanocyte stimulating hormone analogue, is a potential novel neuroprotective agent. We set out to assess the feasibility and safety of afamelanotide for the first time in AIS patients. Methods: AIS patients within 24 h of onset, with perfusion abnormality on imaging (Tmax) and otherwise ineligible for revascularisation therapies were enrolled. Afamelanotide 16 mg implants were administered subcutaneously on Day 0 (D0, day of recruitment), D1 and repeated on D7 and D8, if not well recovered. Treatment emergent adverse events (TEAEs) and neurological assessments were recorded regularly up to D42. Magnetic resonance imaging (MRI) with FLAIR sequences were also performed on D3 and D9. Results: Six patients (5 women, median age 81, median NIHSS 6) were recruited. Two patients received 4 doses and four patients received 2. One patient (who received 2 doses), suffered a fatal recurrent stroke on D9 due to a known complete acute internal carotid artery occlusion, assessed as unrelated to the study drug. There were no other local or major systemic TEAEs recorded. In all surviving patients, the median NIHSS improved from 6 to 2 on D7. The median Tmax volume on D0 was 23 mL which was reduced to a FLAIR volume of 10 mL on D3 and 4 mL on D9. Conclusions: Afamelanotide was well tolerated and safe in our small sample of AIS patients. It also appears to be associated with good recovery and radiological improvement of salvageable tissue which needs to be tested in randomized studies. ClinicalTrials.gov Identifier: NCT04962503, First posted 15/07/2021. [ABSTRACT FROM AUTHOR]

Objective To observe the efficacy of Q switch ruby laser combined with tranexamic acid for melasma and its effects on melanin metabolism. Methods A total of 60 patients with melasma were divided into three groups: Drug group (oral tranexamic acid 500 mg/day for six months), the laser group (Q switched ruby laser, once every 2 weeks for 2 months), combination therapy (laser plus tranexamic acid, same method and course of treatment as in single modality). Results Combination therapy significantly lowered Melasma Area and Severity Index compared to single treatment modality [(67.02±18.58)% vs. (53.13±20.66)% in laser and (53.97±18.48)% in drug group), both P0.05). After the treatment, levels of Tyr and MSH in the combination therapy were lower than that in the laser and drug groups, while MT levels was higher in the combination therapy than in the laser and drug groups (all P

Glial cells have emerged as key players in the central control of energy balance and etiology of obesity. Astrocytes play a central role in neural communication via the release of gliotransmitters. Acyl-CoA-binding protein-derived (ACBP-derived) endozepines are secreted peptides that modulate the [GABA.sub.A] receptor. In the hypothalamus, ACBP is enriched in arcuate nucleus (ARC) astrocytes, ependymocytes, and tanycytes. Central administration of the endozepine octadecaneuropeptide (ODN) reduces feeding and improves glucose tolerance, yet the contribution of endogenous ACBP in energy homeostasis is unknown. We demonstrated that ACBP deletion in GFAP* astrocytes, but not in Nkx2.1-lineage neural cells, promoted diet-induced hyperphagia and obesity in both male and female mice, an effect prevented by viral rescue of ACBP in ARC astrocytes. [ACBP.sup.+] astrocytes were observed in apposition with proopiomelanocortin (POMC) neurons, and ODN selectively activated POMC neurons through the ODN GPCR but not [GABA.sub.A], and suppressed feeding while increasing carbohydrate utilization via the melanocortin system. Similarly, ACBP overexpression in ARC astrocytes reduced feeding and weight gain. Finally, the ODN GPCR agonist decreased feeding and promoted weight loss in ob/ob mice. These findings uncover ACBP as an ARC gliopeptide playing a key role in energy balance control and exerting strong anorectic effects via the central melanocortin system., Introduction In the central nervous system, the hypothalamus is a key site for the detection and integration of circulating metabolic signals. In turn, the hypothalamus initiates appropriate neuroendocrine and behavioral [...]

Objective(s): Malignant melanoma is the most lethal type of skincancers with unfavorable prognosis. Alpha-MSH peptide analogues havea high affinity for melanocortine-1 (MC1) receptors on melanocytes overexpressing in malignant melanoma cells. Pre-clinical studies have shownpromising results for radiolabeled MSH imaging in this malignancy. Thepurpose of this study is to assess the diagnostic value of 99mTc-α-MSHimaging in malignant melanoma.Methods: Twenty-one patients (13 men) with pathologically confirmedmalignant melanoma with or without metastatic distribution wereincluded in this study. 740-1110 MBq 99mTc-α-MSH was injected and wholebody scans were performed 20, 120 and 240 minutes post injection andwere assessed both qualitatively and semi-quantitatively using target (T)to background (BG) ratio.Results: The T/BG ratio for the primary tumor bed was 2.51±2.26,2.56±2.48 and 1.92±1.79 minutes in the whole body scans 20, 120 and 240minutes post injection, respectively. The sensitivity, specificity, negativeand positive predictive values were 75%, 80%, 50% and 92% for primarylesion and 25%, 100%, 68% and 100% for distant metastasis, respectively.Conclusion: 99mTc-α-MSH is a newly introduced agent for diagnosisof tumoral lesions in malignant melanoma. Our study showed a highsensitivity with this modality in primary lesions as well as lymph nodeinvolvements. However the detection rate was not high in distantmetastasis. The preliminary results are promising especially as a newcomplementary imaging method in management of malignant melanoma.

Leptin, a hormone produced in white adipose tissue, acts in the brain to communicate fuel status, suppress appetite following a meal, promote energy expenditure and maintain blood glucose stability.sup.1,2. Dysregulation of leptin or its receptors (LEPR) results in severe obesity and diabetes.sup.3-5. Although intensive studies on leptin have transformed obesity and diabetes research.sup.2,6, clinical applications of the molecule are still limited.sup.7, at least in part owing to the complexity and our incomplete understanding of the underlying neural circuits. The hypothalamic neurons that express agouti-related peptide (AGRP) and pro-opiomelanocortin (POMC) have been hypothesized to be the main first-order, leptin-responsive neurons. Selective deletion of LEPR in these neurons with the Cre-loxP system, however, has previously failed to recapitulate, or only marginally recapitulated, the obesity and diabetes that are seen in LEPR-deficient Lepr.sup.db/db mice, suggesting that AGRP or POMC neurons are not directly required for the effects of leptin in vivo.sup.8-10. The primary neural targets of leptin are therefore still unclear. Here we conduct a systematic, unbiased survey of leptin-responsive neurons in streptozotocin-induced diabetic mice and exploit CRISPR-Cas9-mediated genetic ablation of LEPR in vivo. Unexpectedly, we find that AGRP neurons but not POMC neurons are required for the primary action of leptin to regulate both energy balance and glucose homeostasis. Leptin deficiency disinhibits AGRP neurons, and chemogenetic inhibition of these neurons reverses both diabetic hyperphagia and hyperglycaemia. In sharp contrast to previous studies, we show that CRISPR-mediated deletion of LEPR in AGRP neurons causes severe obesity and diabetes, faithfully replicating the phenotype of Lepr.sup.db/db mice. We also uncover divergent mechanisms of acute and chronic inhibition of AGRP neurons by leptin (presynaptic potentiation of GABA ([gamma]-aminobutyric acid) neurotransmission and postsynaptic activation of ATP-sensitive potassium channels, respectively). Our findings identify the underlying basis of the neurobiological effects of leptin and associated metabolic disorders.A subset of neurons in the hypothalamus is identified as the primary site of action for regulating energy balance and glucose homeostasis by leptin., Author(s): Jie Xu [sup.1] , Christopher L. Bartolome [sup.1] [sup.2] , Cho Shing Low [sup.1] [sup.3] , Xinchi Yi [sup.1] , Cheng-Hao Chien [sup.1] , Peng Wang [sup.1] , Dong [...]

Ashley M Lane,1 Jerome T McKay,2 Herbert L Bonkovsky1 1Department of Internal Medicine, Section on Gastroenterology; 2Department of Microbiology and Immunology, Wake Forest University School of Medicine, Winston-Salem, NC, USAAbstract: Erythropoietic protoporphyria (EPP) and the phenotypically similar disease X-linked protoporphyria (XLPP) are inherited cutaneous porphyrias characterized clinically by acute non-blistering photosensitivity, intolerance to sunlight, and significantly reduced quality of life. They are due to marked overproduction of protoporphyrin (PP) chiefly by erythroblasts and reticulocytes. In EPP, the underlying genetic defect is in the ferrochelatase gene, which encodes the final enzyme in the heme synthetic pathway. In XLPP, the genetic defect is a gain-of-function mutation, usually a four-base deletion, in the gene that encodes the enzyme 5-aminolevulinic acid synthase-2, the first and rate-controlling enzyme of heme synthesis in developing red blood cells. The excess PP causes acute and painful photosensitivity, being activated by light in the long ultraviolet to blue spectrum (380–420 nm, the Soret band). Although several treatments have been proposed, presently no very effective treatment exists for EPP or XLPP. Afamelanotide (Scenesse®) is a first-in-class synthetic analog of α-melanocyte stimulating hormone. Afamelanotide mimics the naturally occurring hormone to increase skin pigmentation by increasing melanin production in melanocytes, resulting in increased sunlight tolerance in those with EPP/XLPP. Afamelanotide is currently approved for use in the European Union and Switzerland, and it is under review in the United States by the Food and Drug Administration for use in patients with EPP/XLPP. This paper provides a review of the clinical characteristics and current therapies for EPP/XLPP. We discuss the pharmacology, clinical efficacy, safety, and tolerability of afamelanotide and summarize the results of several key Phase II and III clinical trials. These data indicate that afamelanotide is a promising therapy for those with these debilitating diseases.Keywords: afamelanotide, eumelanin, heme, melanocyte stimulating hormone, photosensitivity, porphyria

Five experiments were performed to test the hypothesis that α-melanocyte–stimulating hormone (MSH) is secreted in response to various stressors in horses similar to prolactin, growth hormone, and adrenocorticotropin (ACTH). There was considerable variation in resting concentrations of MSH and in the degree of stimulation in responders; thus all data sets were tested for heterogeneity of variance and corrected for as needed before analysis. In experiment 1, 12 mares were used in a switchback design to test the effect of a 2-minute exercise bout on MSH secretion. Plasma MSH concentrations were constant when mares were not exercised but increased (P <.05) immediately (2 minutes) after exercise and were still elevated 5 minutes later. In experiment 2, six mares were twitched for 2 minutes and six mares were not twitched. Twitching stimulated (P <.05) both MSH and ACTH relative to controls. Experiments 3, 4, and 5 tested the acute effects of intravenous injection of epinephrine at 5 μg/kg of body weight, intravenous injection of 100 μg substance P, and intramuscular injection of 10 mg prostaglandin-F 2α in mares compared to controls (6, 5, and 6 mares per treatment group, respectively). Concentrations of MSH increased (P ≤.05) after treatment in all three experiments. Plasma concentrations of ACTH also increased (P <.01) after administration of epinephrine and prostaglandin-F 2α in experiments 3 and 5; plasma ACTH was not measured in experiment 1 or 4 because we have previously reported that exercise and substance P stimulate plasma ACTH concentrations. As hypothesized, MSH is secreted in response to various stimuli similar to that observed previously for prolactin, growth hormone, and ACTH. • Five experiments were performed to test the hypothesis that α-melanocyte–stimulating hormone (MSH) is secreted in response to various stressors in horses similar to prolactin, growth hormone, and adrenocorticotropin (ACTH). • There was considerable variation in resting concentrations of MSH and in the degree of stimulation in responders. • Concentrations of MSH were increased by exercise, twitching, and epinephrine administration, substance P administration, and prostaglandin-F 2α administration. • Twitching, epinephrine administration, and prostaglandin-F 2α administration also stimulated ACTH secretion. • The role of MSH, and the reason for its secretion in response to these stimuli, is still unclear. [ABSTRACT FROM AUTHOR]

Presently, tissue engineering is employed in the restoration and repair of tissue defects. Degradable scaffolds, stem cells and stimulating factors are employed in this method. In this study, the effect of melanocyte-stimulating hormone (MSH) and/or hydroxyapatite (HA) on proliferation, osteoblast differentiation, and mineralization of human dental pulp stem cells (hDPSCs) seeded on PLLA-PCL nanofibrous scaffolds was evaluated. For this aim, PLLA-PCL-HA nanofibrous scaffolds were fabricated using electrospinning method. FE-SEM images exhibited that all nanofibers had bead-free morphologies with average diameters ranging from 150-205 nm. Human DPSCs seeded into PLLA-PCL nanofibers were treated with MSH. Cell viability, proliferation, morphology, osteogenic potential, and the expression of tissue-specific genes were assessed by means of MTT assay, FE-SEM, alizarin red S staining, and RT-PCR analysis. hDPSCs exhibited improved adhesion and proliferation capacity on the PLLA-PCL-HA nanofibers treated with MSH compared to other groups (p<0.05). Additionally, PLLA-PCL-HA nanofibers treated with MSH exhibited significantly higher mineralization and alkaline phosphatase activity than other groups. RT-PCR results confirmed that PLLA-PCL-HA nanofibers enriched with MSH could significantly unregulated the gene expression of BMP2, osteocalcin, RUNX2 and DSPP that correlated to osteogenic differentiation (p<0.05). Based on results, incorporation of HA nanoparticles in PLLA-PCL nanofibers and addition of MSH in media exhibited synergistic effects on the adhesion, proliferation, and osteogenesis differentiation of hDPSCs, and therefore assumed to be a favorable scaffold for bone tissue engineering applications. [ABSTRACT FROM AUTHOR]

Objective(s): Malignant melanoma is the most lethal type of skin cancers with unfavorable prognosis. Alpha-MSH peptide analogues have a high affinity for melanocortine-1 (MC1) receptors on melanocytes over expressing in malignant melanoma cells. Pre-clinical studies have shown promising results for radiolabeled MSH imaging in this malignancy. The purpose of this study is to assess the diagnostic value of 99mTc-a-MSH imaging in malignant melanoma. Methods: Twenty-one patients (13 men) with pathologically confirmed malignant melanoma with or without metastatic distribution were included in this study. 740-1110 MBq 99mTc-a-MSH was injected and whole body scans were performed 20, 120 and 240 minutes post injection and were assessed both qualitatively and semi-quantitatively using target (T) to background (BG) ratio. Results: The T/BG ratio for the primary tumor bed was 2.51±2.26, 2.56±2.48 and 1.92±1.79 minutes in the whole body scans 20, 120 and 240 minutes post injection, respectively. The sensitivity, specificity, negative and positive predictive values were 75%, 80%, 50% and 92% for primary lesion and 25%, 100%, 68% and 100% for distant metastasis, respectively. Conclusion: 99mTc-a-MSH is a newly introduced agent for diagnosis of tumoral lesions in malignant melanoma. Our study showed a high sensitivity with this modality in primary lesions as well as lymph node involvements. However the detection rate was not high in distant metastasis. The preliminary results are promising especially as a new complementary imaging method in management of malignant melanoma. [ABSTRACT FROM AUTHOR]

Background There is interest in using convolutional neural networks (CNNs) to analyze medical imaging to provide computer-aided diagnosis (CAD). Recent work has suggested that image classification CNNs may not generalize to new data as well as previously believed. We assessed how well CNNs generalized across three hospital systems for a simulated pneumonia screening task. Methods and findings A cross-sectional design with multiple model training cohorts was used to evaluate model generalizability to external sites using split-sample validation. A total of 158,323 chest radiographs were drawn from three institutions: National Institutes of Health Clinical Center (NIH; 112,120 from 30,805 patients), Mount Sinai Hospital (MSH; 42,396 from 12,904 patients), and Indiana University Network for Patient Care (IU; 3,807 from 3,683 patients). These patient populations had an age mean (SD) of 46.9 years (16.6), 63.2 years (16.5), and 49.6 years (17) with a female percentage of 43.5%, 44.8%, and 57.3%, respectively. We assessed individual models using the area under the receiver operating characteristic curve (AUC) for radiographic findings consistent with pneumonia and compared performance on different test sets with DeLong's test. The prevalence of pneumonia was high enough at MSH (34.2%) relative to NIH and IU (1.2% and 1.0%) that merely sorting by hospital system achieved an AUC of 0.861 (95% CI 0.855-0.866) on the joint MSH-NIH dataset. Models trained on data from either NIH or MSH had equivalent performance on IU (P values 0.580 and 0.273, respectively) and inferior performance on data from each other relative to an internal test set (i.e., new data from within the hospital system used for training data; P values both Conclusion Pneumonia-screening CNNs achieved better internal than external performance in 3 out of 5 natural comparisons. When models were trained on pooled data from sites with different pneumonia prevalence, they performed better on new pooled data from these sites but not on external data. CNNs robustly identified hospital system and department within a hospital, which can have large differences in disease burden and may confound predictions., Author(s): John R. Zech 1, Marcus A. Badgeley 2, Manway Liu 2, Anthony B. Costa 3, Joseph J. Titano 4, Eric Karl Oermann 3,* Introduction There is significant interest in [...]

Byline: Oluwagbemiga. Adeodu, Oluwatosin. Olorunmoteni, Saheed. Oseni, Efere. Obuotor Background: Beta (ß)-endorphins are endogenous neuropeptides found in the plasma and cerebrospinal fluid (CSF) of humans but there have been reports [...]

Highlights: [•] We characterise the melanocortin-1 receptor of wildtype and melanic grey squirrel. [•] We show that agouti signalling protein is an inverse agonist to the wildtype receptor. [•] We show that agouti signalling protein is an agonist to the mutant receptor. [•] Models predict the mutant receptor has a shorter extracellular loop 1 than wildtype. [•] We propose that the shorter loop allows agouti signalling protein to activate the mutant receptor. [ABSTRACT FROM AUTHOR]